Farnesyl protein transferase inhibitors

ABSTRACT

Disclosed are compounds of the formula:  
                 
 
     wherein R 13  represents an imidazole ring; R 14  represents a carbamate, urea, amide or sulfonamide group; R 8  represents H when the alkyl chain between the amide group and the R 13  imidazole group is substituted, or R 8  represents a substituent such as arylalkyl, heteroarylalkyl or cycloalkyl; and the remaining substituents are as defined herein.  
     Also disclosed are compounds wherein R 8  is H, and the alkyl chain between the amide group and the R 13  imidazole group is unsubstituted.  
     Also disclosed is a method of treating cancer and a method of inhibiting farnesyl protein transferase using the disclosed compounds.

BACKGROUND

[0001] WO 95/10516, published Apr. 20, 1995, WO96/31478, published Oct. 10, 1996, and copending application Ser. No. 09/094687 filed Jun. 15, 1998 discloses tricyclic compounds useful for inhibiting farnesyl protein transferase.

[0002] In view of the current interest in inhibitors of farnesyl protein transferase, a welcome contribution to the art would be compounds useful for the inhibition of farnesyl protein transferase. Such a contribution is provided by this invention.

SUMMARY OF THE INVENTION

[0003] This invention provides compounds useful for the inhibition of farnesyl protein transferase (FPT). The compounds of this invention are represented by the formula:

[0004] or a pharmaceutically acceptable salt or solvate thererof, wherein:

[0005] one of a, b, c and d represents N or N⁺O⁻, and the remaining a, b, c and d groups represent CR¹ or CR²; or

[0006] each of a, b, c, and d are independently selected from CR¹ or CR²;

[0007] X represents N or CH when the optional bond (represented by the dotted line) is absent, and represents C when the optional bond is present;

[0008] the dotted line between carbon atoms 5 and 6 represents an optional bond, such that when a double bond is present, A and B independently represent —R¹⁵, halo, —OR¹⁶, —OCO₂R¹⁶ or —OC(O)R¹⁵, and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H₂, —(OR¹⁶)₂, H and halo, dihalo, alkyl and H, (alkyl)₂, —H and —OC(O)R¹⁵, H and —OR¹⁵, ═O, aryl and H, ═NOR¹⁵ or —O—(CH₂)_(p)—O— wherein p is 2, 3 or 4;

[0009] each R¹ and each R² is independently selected from H, halo, —CF₃, —OR¹⁵ (e.g., —OCH₃), —COR¹⁵, —SR¹⁵ (e.g., —SCH₃ and —SCH₂C₆H₅), —S(O)_(t)R¹⁶ (wherein t is 0, 1 or 2, e.g., —SOCH₃ and —SO₂CH₃), —N(R¹⁵)₂, —NO₂, —OC(O)R¹⁵, —CO₂R¹⁵, —OCO₂R¹⁶, —CN, —NR¹⁵COOR¹⁶, —SR¹⁶C(O)OR¹⁶ (e.g., —SCH₂CO₂CH₃), —SR¹⁶N(R¹⁷)₂ (provided that R¹⁶ in —SR¹⁶N(R¹⁷)₂ is not —CH₂—) wherein each R¹⁷ is independently selected from H or —C(O)OR¹⁶ (e.g., —S(CH₂)₂NHC(O)O-t-butyl and —S(CH₂)₂NH₂), benzotriazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazol-5-ylthio (e.g., alkyl substituted tetrazol-5-ylthio such as 1-methyl-tetrazol-5-ylthio), alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo, —OR¹⁵ or —CO₂R¹⁵;

[0010] R³ and R⁴ are the same or different and each independently represents H, any of the substituents of R¹ and R², or R³ and R⁴ taken together represent a saturated or unsaturated C₅-C₇ fused ring to the benzene ring (Ring III);

[0011] R⁵, R⁶, and R⁷ each independently represents H, —CF₃, —COR¹⁵, alkyl or aryl, said alkyl or aryl optionally being substituted with —OR¹⁵, —SR¹⁵, —S(O)_(t)R¹⁶, —NR¹⁵COOR¹⁶, —N(R¹⁵)₂, —NO₂, —COR¹⁵, —OCOR¹⁵, —OCO₂R¹⁶, —CO₂R¹⁵, OPO₃R¹⁵, or R⁵ is combined with R⁶ to represent ═O or ═S;

[0012] R⁸ is selected from: H, C₃ to C₄ alkyl (preferably branched chain alkyl, and most preferably C₄ to C₇ branched chain alkyl), aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, substituted alkyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl;

[0013] the substutuents for the R⁸ substituted groups being selected from: alkyl, aryl, arylalkyl, cycloalkyl, —N(R¹⁸)₂, —OR¹⁸, cycloalkyalkyl, halo, CN, —C(O)N(R¹⁸)₂, —SO₂N(R¹⁸)₂ or —CO₂R¹⁸; provided that the —OR¹⁸ and —N(R¹⁸)₂ substituents are not bound to the carbon that is bound to the N of the —C(O)NR⁸-moiety;

[0014] each R¹⁸ is independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl;

[0015] R⁹ and R¹⁰ are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or —CON(R¹⁸)₂ (wherein R¹⁸ is as defined above); and the substitutable R⁹ and R¹⁰ groups are optionally substituted with one or more (e.g., 1-3) substituents selected from: alkyl (e.g., methyl, ethyl, isopropyl, and the like), cycloalkyl, arylalkyl, or heterarylalkyl (i.e., the R⁹ and/or R¹⁰ groups can be unsubtituted or can be substituted with 1-3 of the substitutents described above, except when R⁹ and/or R¹⁰ is H); or

[0016] R⁹ and R¹⁰ together with the carbon atom to which they are bound, form a C₃ to C₆ cycloalkyl ring;

[0017] R¹¹ and R¹² are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, —CON(R¹⁸)₂—OR¹⁸ or —N(R¹⁸)₂; wherein R¹⁸ is as defined above; provided that the —OR¹⁸ and —N(R¹⁸)₂ groups are not bound to a carbon atom that is adjacent to a nitrogen atom; and wherein said substitutable R¹¹ and R¹² groups are optionally substituted with one or more (e.g., 1-3) substituents selected from: alkyl (e.g., methyl, ethyl, isopropyl, and the like), cycloalkyl, arylalkyl, or heterarylalkyl; or

[0018] R¹¹ and R¹² together with the carbon atom to which they are bound, form a C₃ to C₆ cycloalkyl ring;

[0019] R¹³ is an imidazolyl ring selected from:

[0020]  wherein R¹⁹ is selected from: (1) H, (2) alkyl, (3) alkyl, (4) aryl, (5) arylalkyl, (6) substituted arylalkyl wherein the substituents are selected from halo (e.g., F and Cl) or CN, (7) —C(aryl)₃ (e.g., —C(phenyl)₃, i.e., trityl) or (8) cycloalkyl;

[0021] said imidazolyl ring 2.0 or 2.1 optionally being substituted with one or two substituents and said imidazole ring 4.0 optionally being substituted with 1-3 substituents and said imidazole ring 4.1 being optionally substituted with one substituent wherein said optional substituents for rings 2.0, 2.1, 4.0 and 4.1 are bound to the carbon atoms of said imidazole rings and said optional substituents are independently selected from: —NHC(O)R¹⁸, —C(R³⁴)₂OR³⁵, —OR¹⁸, —SR¹⁸, F, Cl, Br, alkyl, aryl, arylalkyl, cycloalkyl, or —N(R¹⁸)₂ (wherein each R¹⁸ is independently selected); R¹⁸ is as defined above; each R³⁴ is independently selected from H or alkyl (preferably —CH₃), preferably H; R³⁵ is selected from H, —C(O)OR²⁰, or —C(O)NHR²⁰, and R²⁰ is as defined below (preferably R²⁰ is alkyl or cycloalkyl, most preferably cyclopentyl or cyclohexyl); Q represents an aryl ring (e.g., phenyl), a cycloalkyl ring (e.g., cyclopentyl or cyclohexyl) or a heteroaryl ring (e.g., furanyl, pyrrolyl, thienyl, oxazolyl or thiazolyl), said Q is optionally substituted with 1 to 4 substituents inedependently selected from halo (e.g., F or Cl), alkyl, aryl, —OR¹⁸, —N(R¹⁸)₂ (wherein each R¹⁸ is independently selected), —OC(O)R¹⁸, or —C(O)N(R¹⁸)₂ (wherein each R¹⁸ is independently selected), and wherein R¹⁸ is as defined above; (examples of the —C(R³⁴)₂OR³⁵ group include —CH₂OH, —CH₂OC(O)OR²⁰ and —CH₂OC(O)NHR²⁰);

[0022] R¹⁴ is selected from:

[0023] R¹⁵ is selected from: H, alkyl, aryl or arylalkyl;

[0024] R¹⁶ is selected from: alkyl or aryl;

[0025] R²⁰ is selected from: H, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl, provided that R²⁰ is not H when R¹⁴ is group 5.0 or 8.0;

[0026] when R²⁰ is other than H, then said R²⁰ group is optionally substituted with one or more (e.g., 1-3) substituents selected from: halo, alkyl, aryl, —OC(O)R¹⁸ (e.g., —OC(O)CH₃), —OR¹⁸ or —N(R¹⁸)₂, wherein each R¹⁸ group is the same or different, and wherein R¹⁸ is as defined above, provided that said optional substituent is not bound to a carbon atom that is adjacent to an oxygen or nitrogen atom;

[0027] R²¹ is selected from: H, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl;

[0028] when R²¹ is other than H, then said R²¹ group is optionally substituted with one or more (e.g., 1-3) substituents selected from: halo, alkyl, aryl, —OR¹⁸ or —N(R¹⁸)₂, wherein each R¹⁸ group is the same or different, and wherein R¹⁸ is as defined above, provided that said optional substituent is not bound to a carbon atom that is adjacent to an oxygen or nitrogen atom;

[0029] n is 0-5;

[0030] each R³² and R³³ for each n (i.e., for each —C(R³²)(R³³)— group), are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, —CON(R¹⁸)₂, —OR¹⁸ or —N(R¹⁸)₂; wherein R¹⁸ is as defined above; and wherein said substitutable R³² and R³³ groups are optionally substituted with one or more (e.g., 1-3) substituents selected from: alkyl (e.g., methyl, ethyl, isopropyl, and the like), cycloalkyl, arylalkyl, or heterarylalkyl; or

[0031] R³² and R³³ together with the carbon atom to which they are bound, form a C₃ to C₆ cycloalkyl ring; and

[0032] R³⁶ is selected from branched ally, unbranched alkyl cycloalkyl, heterocycloalkyl, or aryl (e.g., phenyl); and

[0033] provided that:

[0034] (1) when R¹⁴ is selected from: group 6.0, 7.0, 7.1 or 8.0, and X is N, then R⁸ is selected from: C₃ to C₁₀ alkyl, substituted C₃ to C₁₀ alkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl; and

[0035] (2) when R¹⁴ is selected from: group 6.0, 7.0, 7.1 or 8.0, and X is N, and R⁸ is H, then the alkyl chain between R¹³ (i.e., imidazole ring 2.0, 4.0 or 4.1) and the amide moiety (i.e., the —C(O)NR¹⁸ group) is substituted, i.e.,: (a) at least one of R⁹, R¹⁰, R¹¹, R¹², R³², or R³³ is other than H, and/or (b) R⁹ and R¹⁰, and/or R¹¹ and R¹², are taken together to form a cycloalkyl ring.

[0036] This invention also provides compounds of formula 1.0, as described above, wherein when R¹⁴ is group 5.0, and X is N, and R⁸ is H, then the alkyl chain between R¹³ (i.e., imidazole ring 2.0, 4.0 or 4.1) and the amide moiety (i.e., the —C(O)NR¹⁸ group) is substituted, i.e.,: (a) at least one of R⁹, R¹⁰, R¹¹, R¹², R³², or R³³ is other than H, and/or (b) R⁹ and R¹⁰, and/or R¹¹ and R¹², are taken together to form a cyloalkyl ring.

[0037] The compounds of this invention: (i) potently inhibit farnesyl protein transferase, but not geranylgeranyl protein transferase I, in vitro; (ii) block the phenotypic change induced by a form of transforming Ras which is a farnesyl acceptor but not by a form of transforming Ras engineered to be a geranylgeranyl acceptor; (iii) block intracellular processing of Ras which is a farnesyl acceptor but not of Ras engineered to be a geranylgeranyl acceptor; and (iv) block abnormal cell growth in culture induced by transforming Ras.

[0038] The compounds of this invention inhibit farnesyl protein transferase and the farnesylation of the oncogene protein Ras. Thus, this invention further provides a method of inhibiting farnesyl protein transferase, (e.g., ras farnesyl protein transferase) in mammals, especially humans, by the administration of an effective amount of the tricyclic compounds described above. The administration of the compounds of this invention to patients, to inhibit farnesyl protein transferase, is useful in the treatment of the cancers described below.

[0039] This invention provides a method for inhibiting or treating the abnormal growth of cells, including transformed cells, by administering an effective amount of a compound of this invention. Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs.

[0040] This invention also provides a method for inhibiting or treating tumor growth by administering an effective amount of the tricyclic compounds, described herein, to a mammal (e.g., a human) in need of such treatment. In particular, this invention provides a method for inhibiting or treating the growth of tumors expressing an activated Ras oncogene by the administration of an effective amount of the above described compounds. Examples of tumors which may be inhibited or treated include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, melanoma, breast cancer and prostate cancer.

[0041] It is believed that this invention also provides a method for inhibiting or treating proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes—i.e., the Ras gene itself is not activated by mutation to an oncogenic form—with said inhibition or treatment being accomplished by the administration of an effective amount of the tricyclic compounds described herein, to a mammal (e.g., a human) in need of such treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes (e.g., neu, src, abl, lck, and fyn), may be inhibited or treated by the tricyclic compounds described herein.

[0042] The tricyclic compounds useful in the methods of this invention inhibit or treat the abnormal growth of cells. Without wishing to be bound by theory, it is believed that these compounds may function through the inhibition of G-protein function, such as ras p21, by blocking G-protein isoprenylation, thus making them useful in the treatment of proliferative diseases such as tumor growth and cancer. Without wishing to be bound by theory, it is believed that these compounds inhibit ras farnesyl protein transferase, and thus show antiproliferative activity against ras transformed cells.

DETAILED DESCRIPTION OF THE INVENTION

[0043] As used herein, the following terms are used as defined below unless otherwise indicated:

[0044] MH⁺-represents the molecular ion plus hydrogen of the molecule in the mass spectrum;

[0045] BOC-represents tert-butyloxycarbonyl;

[0046] CBZ-represents —C(O)OCH₂C₆H₅ (i.e., benzyloxycarbonyl);

[0047] CH₂Cl₂-represents dichloromethane;

[0048] CIMS-represents chemical ionization mass spectrum;

[0049] DEAD-represents diethylazodicarboxylate;

[0050] DEC-represents EDCI which represents 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride;

[0051] DMF-represents N,N-dimethylformamide;

[0052] Et-represents ethyl;

[0053] EtOAc-represents ethyl acetate;

[0054] EtOH-represents ethanol;

[0055] HOBT-represents 1-hydroxybenzotriazole hydrate;

[0056] IPA-represents isopropanol;

[0057] iPrOH-represents isopropanol;

[0058] Me-represents methyl;

[0059] MeOH-represents methanol;

[0060] MS-represents mass spectroscopy;

[0061] NMM-represents N-methylmorpholine;

[0062] Ph-represents phenyl;

[0063] Pr-represents propyl;

[0064] TBDMS-represents tert-butyldimethylsilyl;

[0065] TEA-represents triethylamine;

[0066] TFA-represents trifluoroacetic acid;

[0067] THF-represents tetrahydrofuran;

[0068] Tr-represents trityl;

[0069] alkyl-represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms;

[0070] acyl-represents a G—C(O)— group wherein G represents alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, —O-alkyl, —O-aryl, or NR²⁵R²⁶ wherein R²⁵ and R²⁶ are independently selected from alkyl or aryl;

[0071] arylalkyl-represents an alkyl group, as defined above, substituted with an aryl group, as defined below, such that the bond from another substituent is to the alkyl moiety;

[0072] aryl-(including the aryl portion of arylalkyl)-represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (e.g., aryl is a phenyl ring), with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment, said carbocyclic group being optionally substituted (e.g., 1 to 3) with one or more of halo, alkyl, hydroxy, alkoxy, phenoxy, CF₃, —C(O)N(R¹⁸)₂, —SO₂R¹⁸, —SO₂N(R¹⁸)₂, amino, alkylamino, dialkylamino, —COOR²³ or —NO₂, wherein R²³ represents alkyl or aryl; and

[0073] cycloalkyl-represents saturated carbocyclic rings of from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms, said cycloalkyl ring being optionally substituted with one or more (e.g., 1, 2 or 3) alkyl groups (e.g., methyl or ethyl) and when there is more than one alkyl group each alkyl group is independently selected;

[0074] cycloalkylalkyl-represents a cycloalkyl group, as defined above, substituted with an alkyl group, as defined above, such that the bond from another substituent is to the alkyl moiety;

[0075] halo-represents fluoro, chloro, bromo and iodo;

[0076] heteroaralkyl-represents an alkyl group, as defined above, substituted with a heteroaryl group, as defined below, such that the bond from another substituent is to the alkyl moiety;

[0077] heteroaryl-represents cyclic groups, optionally substituted with R³ and R⁴, having at least one heteroatom selected from O, S or N, said heteroatom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic groups preferably containing from 2 to 14 carbon atoms, e.g., 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-thiazolyl, 2-, 4- or 5-imidazolyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, 3- or 4-pyridazinyl, 3-, 5- or 6-[1,2,4-triazinyl], 3- or 5-[1,2,4-thiadizolyl], 2-, 3-, 4-, 5-, 6- or 7-benzofuranyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, triazolyl,2-, 3- or 4-pyridyl or pyridyl N-oxide (optionally substituted with R³ and R⁴), wherein pyridyl N-oxide can be represented as:

[0078] heterocycloalkyl-represents a saturated, branched or unbranched carbocylic ring containing from 3 to 15 carbon atoms, preferably from 4 to 6 carbon atoms, which carbocyclic ring is interrupted by 1 to 3 hetero groups selected from —O—, —S— or —NR²⁴, wherein R²⁴ represents alkyl, aryl, —C(O)N(R¹⁸)₂ wherein R¹⁸ is as above defined (e.g., —C(O)NH₂) or acyl-(suitable heterocycloalkyl groups include 2- or 3-tetrahydrofuranyl, 2- or 3-tetrahydrothienyl, 2-, 3- or 4-piperidinyl, 2- or 3-pyrrolidinyl, 2- or 3-piperizinyl, 2- or 4-dioxanyl, morpholinyl, etc.).

[0079] The positions in the tricyclic ring system are:

[0080] The compounds of formula 1.0 include the 2R and 2S isomers shown below (2R is preferred):

[0081] Examples of R³ substituents include: benzyl, —CH₂C(CH₃)₂, —CH₂-cyclohexyl, —CH₂-cyclopropyl, —(CH₂)₂CH₃,

[0082] Examples of R⁹ and R¹⁰ groups include H and benzl

[0083] Examples of R¹¹ and R¹² groups include: H, —CH₃, —CH₂CH(CH₃)₂, —(CH₂)₃CH₃, benzyl, ethyl, p-chlorophenyl, and —OH.

[0084] Cyclopropyl is an Example of the R¹¹ and R¹² group being taken together with the carbon atom to which they are bound to form a cycloalkyl ring.

[0085] Examples of the optional substituents for the R¹³ moiety include: —CH₃, —CH₂OH, —CH₂OC(O)O-cyclohexyl, —CH₂OC(O)O-cyclopentyl, ethyl, isopropyl, NH₂, and —NHC(O)CF₃.

[0086] Examples of R¹⁹ include: —C(O)NH-cyclohexyl, —C(phenyl)₃, H, methyl or ethyl.

[0087] Examples of R²⁰ for group 5.0 include: t-butyl, ethyl, benzyl, —CH(CH₃)₂, —CH₂CH(CH₃)₂, —(CH₂)₂CH₃, n-butyl, n-hexyl, n-octyl, p-chlorophenyl, cyclohexyl, cyclopentyl,

[0088] Another example of R²⁰ for group 5.0 is

[0089] Examples of R²⁰ and R²¹ for 6.0 include: cyclohexyl, t-butyl, H, —CH(CH₃)₂, ethyl, —(CH₂)₂CH₃, phenyl, benzyl, —(CH₂)₂phenyl, and —CH₃.

[0090] Examples of R²⁰ for 7.0 include: 4-pyridylNO, —OCH₃, —CH(CH₃)₂, -t-butyl, H, propyl, cyclohexyl and

[0091] Examples for R³⁶ for 7.1 include: cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl,

[0092] Examples for R²⁰ for 8.0 include: methyl, i-propyl and cyclohexylmethyl.

[0093] Examples of R³² and R³³ include: H, phenyl, —OH and benzyl.

[0094] Compounds of this invention include compounds of formula 1.0 wherein when R¹⁴ is selected from: group 6.0, 7.0, 7.1 or 8.0, and X is C or CH (preferably CH), then R⁸ is selected from: C₃ to C₁₀ alkyl, substituted C₃ to C₁₀ alkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl.

[0095] Compounds of this invention include compounds of formula 1.0 wherein when R¹⁴ is selected from: group 6.0, 7.0, 7.1 or 8.0, and X is C or CH (preferably CH), and R⁸ is H, then the alkyl chain between R¹³ (i.e., imidazole ring 2.0, 4.0 or 4.1) and the amide moiety (i.e., the —C(O)NR¹⁸ group) is substituted, i.e.,: (a) at least one of R⁹, R¹⁰, R¹¹, R¹², R³², or R³³ is other than H, and/or (b) R⁹ and R¹⁰, and/or R¹¹ and R¹², are taken together to form a cyloalkyl ring.

[0096] Compounds of this invention include compounds of formula 1.0 wherein when R¹⁴ is group 5.0, and X is C or CH (preferably CH), and R⁸ is H, then the alkyl chain between R¹³ (i.e., imidazole ring 2.0, 4.0 or 4.1) and the amide moiety (i.e., the —C(O)NR¹⁸ group) is substituted, i.e.,: (a) at least one of R⁹, R¹⁰, R¹¹, R¹², R³², or R³³ is other than H, and/or (b) R⁹ and R¹⁰, and/or R¹¹ and R¹², are taken together to form a cyloalkyl ring.

[0097] Compounds of this invention include compounds of formula 1.0 wherein when R¹⁴ is selected from: group 6.0, 7.0, 7.1 or 8.0, and X is C or CH (preferably CH), then R⁸ is selected from: arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl.

[0098] Compounds of this invention include compounds of formula 1.0 wherein when R¹⁴ is 5.0 and X is C or CH (preferably CH), then R⁸ is selected from: arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl.

[0099] Compounds of this invention include compounds of formula 1.0 wherein when R¹⁴ is selected from: group 6.0, 7.0, 7.1 or 8.0, and X is N, then R⁸ is selected from: arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl.

[0100] Compounds of this invention include compounds of formula 1.0 wherein when R¹⁴ is 5.0 and X is N, then R⁸ is selected from: arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl.

[0101] Thus, one embodiment of this invention is directed to compounds wherein R¹⁴ is the carbamate group 5.0 and the other substituents are as defined for formula 1.0.

[0102] Another embodiment of this invention is directed to compounds wherein R¹⁴ is the carbamate group 5.0, X is N and the other substituents are as defined for formula 1.0.

[0103] Another embodiment of this invention is directed to compounds wherein R¹⁴ is the carbamate group 5.0, X is C or CH (preferably CH) and the other substituents are as defined for formula 1.0.

[0104] Another embodiment of this invention is directed to compounds wherein R¹⁴ is the carbamate group 5.0, X is N, R⁸ is arylalkyl or substituted arylalkyl (preferably arylalkyl), and the other substituents are as defined for formula 1.0.

[0105] Another embodiment of this invention is directed to compounds wherein R¹⁴ is the carbamate group 5.0, X is N, R⁸ is heteroarylalkyl or substituted heteroarylalkyl (preferably heteroarylalkyl), and the other substituents are as defined for formula 1.0.

[0106] Another embodiment of this invention is directed to compounds wherein R¹⁴ is the carbamate group 5.0, X is N, R⁸ is cycloalkylalkyl or substituted cycloalkylalkyl (preferably cycloalkylalkyl), and the other substituents are as defined for formula 1.0.

[0107] Another embodiment of this invention is directed to compounds wherein R¹⁴ is the carbamate group 5.0, X is C or CH (preferably CH), R⁸ is arylalkyl or substituted arylalkyl (preferably arylalkyl), and the other substituents are as defined for formula 1.0.

[0108] Another embodiment of this invention is directed to compounds wherein R¹⁴ is the carbamate group 5.0, X is C or CH (preferably CH), R⁸ is heteroarylalkyl or substituted heteroarylalkyl (preferably heteroarylalkyl), and the other substituents are as defined for formula 1.0.

[0109] Another embodiment of this invention is directed to compounds wherein R¹⁴ is the carbamate group 5.0, X is C or CH (preferably CH), R⁸ is cycloalkylalkyl or substituted cycloalkylalkyl (preferably cycloalkylalkyl), and the other substituents are as defined for formula 1.0.

[0110] Another embodiment of this invention is directed to compounds wherein when R¹⁴ is group 5.0, and X is C or CH (preferably CH), and R⁸ is H, then the alkyl chain between R¹³ (i.e., imidazole ring 2.0, 4.0 or 4.1) and the amide moiety (i.e., the —C(O)NR¹⁸ group) is substituted, i.e.,: (a) at least one of R⁹, R¹⁰, R¹¹, R¹², R³², or R³³ is other than H, and/or (b) R⁹ and R¹⁰, and/or R¹¹ and R¹², are taken together to form a cyloalkyl ring, and the other substituents are as defined for formula 1.0.

[0111] Another embodiment of this invention is directed to compounds wherein when R¹⁴ is group 5.0, and X is N, and R⁸ is H, then the alkyl chain between R¹³ (i.e., imidazole ring 2.0, 4.0 or 4.1) and the amide moiety (i.e., the —C(O)NR¹⁸ group) is substituted, i.e.,: (a) at least one of R⁹, R¹⁰, R¹¹, R¹², R³², or R³³ is other than H, and/or (b) R⁹ and R¹⁰, and/or R¹¹ and R¹², are taken together to form a cyloalkyl ring, and the other substituents are as defined for formula 1.0.

[0112] Another embodiment of this invention is directed to compounds wherein R¹⁴ is a group selected from: 6.0, 7.0, 7.1 or 8.0, X is N, R⁸ is arylalkyl or substituted arylalkyl (preferably arylalkyl) and the other substituents are as defined for formula 1.0.

[0113] Another embodiment of this invention is directed to compounds wherein R¹⁴ is a group selected from: 6.0, 7.0, 7.1 or 8.0, X is N, R⁸ is heteroarylalkyl or substituted heteroarylalkyl (preferably heteroarylalkyl) and the other substituents are as defined for formula 1.0.

[0114] Another embodiment of this invention is directed to compounds wherein R¹⁴ is a group selected from: 6.0, 7.0, 7.1 or 8.0, X is N, R⁸ is cycloalkylalkyl or substituted cycloalkylalkyl (preferably, cycloalkylalkyl) and the other substituents are as defined for formula 1.0.

[0115] Another embodiment of this invention is directed to compounds wherein R¹⁴ is a group selected from: 6.0, 7.0, 7.1 or 8.0, X is C or CH (preferably, CH), R⁸ is arylalkyl or substituted arylalkyl (preferably arylalkyl) and the other substituents are as defined for formula 1.0.

[0116] Another embodiment of this invention is directed to compounds wherein R¹⁴ is a group selected from: 6.0, 7.0, 7.1 or 8.0, X is C or CH (preferably, CH), R⁸ is heteroarylalkyl or substituted heteroarylalkyl (preferably, heteroarylalkyl) and the other substituents are as defined for formula 1.0.

[0117] Another embodiment of this invention is directed to compounds wherein R¹⁴ is a group selected from: 6.0, 7.0, 7.1 or 8.0, X is C or CH (preferably, CH), R⁸ is cycloalkylalkyl or substituted cycloalkylalkyl (preferably, cycloalkylalkyl) and the other substituents are as defined for formula 1.0.

[0118] R¹, R², R³, and R⁴ are preferably selected from H or halo, and are more preferably selected from H, Br, F, or Cl, and are most preferably selected from H, Br or Cl. Representative compounds of formula 1.0 include trihalo, dihalo and monohalo substituted compounds, such as, for example: (1) 3,8,10-trihalo; (2) 3,7,8-trihalo; (3) 3,8-dihalo; (4) 8-halo; and (5) 10-halo substituted compounds; wherein each halo is independently selected. Preferred compounds of formula 1.0 include: (1) 3-Br,8-Cl,10-Br-substituted compounds; (2) 3-Br,7-Br,8-Cl-substituted compounds; (3) 3-Br,8-Cl-substituted compounds; (4) 8-Cl-substituted compounds; and (5) 10-Cl-substituted compounds. The 3,8-dihalo compounds are more preferred and the 8-halo compounds are most preferred. Thus, for example, 3-Br,8-Cl substituted compounds are more preferred and 8-Cl substituted compounds are most preferred.

[0119] Substituent a is preferably N or N⁺O⁻ with N being preferred.

[0120] A and B are preferably H₂, i.e., the optional bond is absent and the C₅-C₆ bridge is unsubstituted.

[0121] R⁵, R⁶, and R⁷ are preferably H.

[0122] X is preferably N or CH (i.e., the optional bond is absent), and more preferably X is N.

[0123] R⁸ is preferably selected from: arylalkyl, substituted aryl alkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl or substituted cycloalkylalkyl. Most preferably, R⁸ is selected from: aryl-(C₁-C₄)alkyl, substituted aryl-(C₁-C₄)alkyl, heteroaryl-(C₁-C₄)alkyl, substituted heteroaryl-(C₁-C₄)alkyl, cycloalkyl-(C₁-C₄)alkyl, or substituted cycloalkyl-(C₁-C₄)alkyl. More preferably, R⁸ is selected from: aryl-CH₂—, substituted aryl-CH₂—, heteroaryl-CH₂—, substituted heteroaryl-CH₂—, cycloalkyl-CH₂— or substituted cycloalkyl-CH₂—. Even more preferably, R⁸ is selected from: benzyl, 3-pyridylmethyl, 4-fluoro-benzyl or cyclopropylmethyl, and still more preferably R⁸ is benzyl.

[0124] R¹³ is preferably ring 2.0 or 4.0. When substituted on the substitutable carbon atoms of the imidazole ring, the substituents are generally selected from: —N(R¹⁸)₂, —NHC(O)R¹⁸, —C(R³⁴)₂OR³⁵, or alkyl, e.g., —CH₃, —CH₂OH, —CH₂OC(O)O-cyclohexyl, —CH₂OC(O)O-cyclopentyl, ethyl, isopropyl, NH₂, or —NHC(O)CF₃.

[0125] R¹⁹ is preferably H or alkyl, most preferably H, methyl or ethyl, and more preferably methyl.

[0126] R¹⁴ is preferably a carbamate group represented by substituent 5.0 described above. Preferably, R²⁰ for substituent 5.0 is selected from: alkyl, substituted alkyl, aryl, cycloalkyl, or cycloalkyl substituted with —OH provided that said —OH substituent is not bound to a carbon that is adjacent to an oxygen atom. More preferably R²⁰ for substituent 5.0 is selected from: C₁ to C₄ alkyl and C₅ to C₇ cycloalkyl. Most preferably R²⁰ for substituent 5.0 is selected from: t-butyl, i-propyl and cyclohexyl, with i-propyl and cyclohexyl being more preferred, and with cyclohexyl being even more preferred.

[0127] R²⁰ in substituent 6.0 is preferably selected from: alkyl or cycloalkyl; most preferably t-butyl, isopropyl or cyclohexyl; and more preferably cyclohexyl. R²¹ is preferably selected from: H or alkyl; most preferably H, methyl or isopropyl; and more preferably H.

[0128] R²⁰ in substituent 7.0 is preferably selected from: cycloalkyl or alkyl; most preferably cyclohexyl, cyclopentyl, isopropyl; and more preferably cyclohexyl.

[0129] R³⁶ in substituent 7.1 is preferably selected from: phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0130] and most preferably selected from: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0131] R²⁰ in substituent 8.0 is preferably selected from: alkyl or cycloalkylalkyl; most preferably methyl, isopropyl or cyclohexylmethyl; more preferably methyl or isopropyl: and even more preferably methyl.

[0132] R⁹, R¹⁰, R¹¹, and R¹² are preferably selected from: H, C₁ to C₄ alkyl (e.g., methyl or isopropyl), —CON(R¹⁸)₂ (e.g., —CONH₂), or when R⁹ and R¹⁰, and/or R¹¹ and R¹² are taken together to form a cycloalkyl ring, said ring is preferably cyclopropyl cyclopentyl or cyclohexyl.

[0133] R⁹, R¹⁰, R¹¹, and R¹² are preferably H when R¹⁴ is the carbamate substituent 5.0 and R⁸ is not H.

[0134] When R¹⁴ is selected from substituents 6.0, 7.0, 7.1 and 8.0, and at least one of R⁹, R¹⁰, R¹¹, and R¹² is other than H, then at least one of R⁹, R¹⁰, R¹¹, and R¹² is:

[0135] (I) preferably selected from: (1) C₁ to C₄ alkyl, (2) —CON(R¹⁸)₂ or (3) the cycloalkyl ring formed when R⁹ and R¹⁰, and/or R¹¹ and R¹², are taken together along with the carbon atom to which they are bound;

[0136] (II) most preferably selected from: (1) methyl, (2) isopropyl, (3) —CONH₂ or (4) cyclopropyl; and

[0137] (III) more preferably selected from: (1) R⁹ and R¹⁰ being H, and one of R¹¹ and R¹² being selected from: alkyl (preferably, methyl or isopropyl), and the other being selected from H or alkyl (preferably, methyl); (2) R⁹ and R¹⁰ being H, and R¹¹ and R¹² being taken together to form a cycloalkyl ring (preferably, cyclopropyl); or (3) R¹¹ and R¹² being H, and one of R⁹ and R¹⁰ being —CONH₂, and the other being H.

[0138] Preferred compounds, when at least one of R⁹, R¹⁰, R¹¹, and R¹² is other than H, also include compounds wherein: R⁹ and R¹⁰ are H, and R¹¹ and R¹² are the same or different alkyl, preferably the same, wherein said alkyl is more preferably methyl.

[0139] For compounds of the invention, n is preferably 0-4, more preferably 0-2, and most preferably 0 or 1.

[0140] Preferably, each R³² and R³³ are independently selected from: H, —OR¹⁸, aryl or arylalkyl (e.g., benzyl); most preferably H, —OH or phenyl; and more preferably H.

[0141] Compounds of formula 1.0, wherein X is N or CH, include, with reference to the C-11 bond, the R- and S-isomers:

[0142] Compounds of formula 1.0 also include compounds having the 2S stereochemistry and the C-11 R- or C-11 S-stereochemistry.

[0143] Compounds of this invention include:

[0144] Compounds of the invention also include compounds corresponding to 13.0-15.0, 15.1, 16.0, 16.1, 17.0-19.0, 19.1, 20.0, 20.1, 21.0-23.0, 23.1, 24.0, and 24.1-24.7, except that the compounds have the 2S stereochemistry.

[0145] Compounds of the invention also include compounds corresponding to 13.0-15.0, 15.1, 16.0, 16.1, 17.0-19.0, 19.1, 20.0, 20.1, 21.0-23.0, 23.1, 24.0, and 24.1-24.7, except that Ring I is phenyl instead of pyridyl.

[0146] Compounds of the invention also include compounds corresponding to 13.0-15.0, 15.1, 16.0, 16.1, 17.0-19.0, 19.1, 20.0, 20.1, 21.0-23.0, 23.1, 24.0, and 24.1-24.7, except that Ring I is phenyl instead of pyridyl and the compounds have the 2S stereochemistry.

[0147] Preferred compounds of formula 1.0 include compounds of the formula:

[0148] (i.e., wherein R¹⁴ is the carbamate group 5.0) wherein all substituents are as above defined.

[0149] A preferred compound of formula 25.0 is:

[0150] with formula 27.0:

[0151] being most preferred (wherein all substituents are as defined above).

[0152] Compounds of formula 25.0 include:

[0153] wherein all substituents are as defined above.

[0154] Preferred compounds of formulas 28.0 and 29.0 are those wherein the R¹ to R⁴ substituents are selected to produce trihalo, dihalo and monohalo substituted compounds, as described above.

[0155] Compounds of formula 29.0 are preferred. Most preferred are compounds of formula 29.0 wherein R⁸ is selected from: benzyl, 4-fluorobenzyl, 3-pyridylmethyl or cyclopropylmethyl; R²⁰ is cyclohexyl, i-propyl or t-butyl (more preferred is cyclohexyl), R¹ is Br or H, R³ is Cl, and R⁴ is H. More preferred are compounds of formula 29.0 wherein R⁸ is benzyl, R²⁰ is cyclohexyl, i-propyl or t-butyl (even more preferred cyclohexyl), R¹ is H, R³ is Cl, and R⁴ is H or Cl.

[0156] Preferred compounds of this invention include:

[0157] Most preferred compounds include the compounds

[0158] More preferred compounds include the compounds of Examples 58, 199, 225, 226, 229, 232 and 326. Compounds of Examples 58, 199, 225, 229 and 326 are even more preferred. The compound of Example 225 is even still more preferred. Preferably the compound of Examples 225, 229 and 326 are administered orally.

[0159] This invention is also directed to the compounds of Examples 26, 30, 32, 41, 42, 43, 44, 81, 105, 106, 293, and 309. The compound of Example 309 is preferred.

[0160] This invention is also directed to the compounds of Examples 31, 34, 35, 36, 37, 38, 39, 40, 67, 68, 69, 70, 73, 75, 263, 282, 283, 284, 287, and 289. The compounds of Examples 67, 68, 69, and 70 are preferred.

[0161] This invention is also directed to the compounds of Examples 27, 28, 29, 71, 72, 74, 76, 98, 101, 103, 104, 107, 108, 110, 111, 255, 256, 257, 258, 259, 260, 261, 262, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 285, 286, 286A, 290, 291, 292, 294, 295, 296, 297, 299, 300, 301, 302, and 303. Compounds of Examples 101, 103, 71, 72 Step B, 72 Step C and 259 are preferred

[0162] This invention is also directed to compounds of Examples 33, 279, 280, and 281.

[0163] Lines drawn into the ring systems indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms.

[0164] Certain compounds of the invention may exist in different isomeric (e.g., enantiomers, diastereoisomers, atropisomers) forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms are also included.

[0165] Certain tricyclic compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.

[0166] Certain basic tricyclic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, the pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention.

[0167] All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

[0168] The compounds of formula 1.0 can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemi-hydrate. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention.

[0169] Compounds of the invention may be prepared according to the procedures described in WO 95/10516 published Apr. 20, 1995, WO96/31478 published Oct. 10, 1996, WO 97/23478 published Jul. 3, 1997, U.S. Pat. No. 5,719,148 issued Feb. 17, 1998, and copending application Ser. No. 09/094687 filed Jun. 15, 1998 (see also WO98/57960 published Dec. 23, 1998); the disclosures of each being incorporated herein by reference thereto; and according to the procedures described below.

[0170] Compounds of the invention can be prepared according to the reaction schemes described below.

[0171] In Scheme 1, R¹¹ and R¹² are preferably methyl when H is bound to the amide nitrogen (i.e., when R⁸ in formula 1.0 is H), e.g., 41.0, and are preferably H when the amide nitrogen is substituted (i.e., R⁸ in formula 1.0 is other than H), e.g., 41.1. Those skilled in the art will appreciate that other acylating agents can be used in place of cyclohexyl isocyanate to obtain compounds having different groups bound to the carbonyl group that is bound to the piperazine nitrogen. Those skilled in the art will also appreciate that other esters can be used in place of compound 31.0 to obtain compounds having different carbon chains between the imidazole ring and the —C(O)NH-group.

[0172] Compounds of 41.0 can be prepared beginning with the conjugate addition of imidazole (2-, 4-, and/or 5-substituted) to an appropriately substituted acrylate 31.0 in EtOH at reflux or neat at 90° C. Standard LAH reduction of the ester 32.0 gives the alcohol 33.0 which can be converted to the phthalimide 35.0 via the Mitsunobu reaction. Removal of the phthalimido group with hydrazine in EtOH at reflux gives amine 36.0. This amine readily opens the piperazine anhydride 37.0 with the evolution of CO₂ and subsequent reaction with isocyanates gives the one pot conversion to urea 38.0. Removal of the BOC-group with 50% TFA at room temperature gives the salt 39.0, which can be readily coupled to the tricyclic chloride 40.0 to give the desired product 41.0.

[0173] In Scheme 1, and the Schemes that follow, Y represents C, N or N⁺O⁻ such that there can only be 0-2 Y substituents that are independently selected from N or N⁺O⁻. R^(A) represents the optional substituents in the imidazole ring that are defined for imidazole ring 4.0 above. R^(B) represents the optional substituents defined above for the aryl or heteroaryl groups for R⁸.

[0174] For example, following Reaction Scheme 1, wherein R¹¹ and R¹² are methyl, and using compound 42.0 (see Preparative Example 40 in WO 95/10516 published Apr. 20, 1995)

[0175] The synthesis of the intermediate amine 51.0 begins with the alkylation of the sodium salt of imidazole (or substituted imidazole) 44.0 with 45.0 at 90° C. Standard LAH reduction of the ester 46.0 gives the alcohol 47.0. Tosylation of 47.0 and displacement of tosylate with potassium phthalimide 49.0 in DMF at 90° C. gives the phthaiimido derivative 50.0 which can be readily converted to the amine 51.0 with hydrazine in refluxing EtOH. Compounds wherein R⁸≠H can be prepared as described in Scheme 1.

[0176] Similar to the procedure set forth in Scheme 1 for 36.0 and 36.1, 51.0 and 51.1 in Scheme 2 are reacted to form compounds of formula 1.0. In Scheme 2, R¹¹ and R¹² are preferably methyl when H is bound to the amide nitrogen (i.e., when R⁸ in formula 1.0 is H), and are preferably H when the amide nitrogen is substituted (i.e., R⁸ in formula 1.0 is other than H).

[0177] Compound (±) 52.0 is resolved following procedures similar to those disclosed in WO97/23478 (published Jul. 3, 1997).

[0178] The reagents used in Reaction Scheme 3 are: Reaction Step a: Isatoic anhydride/methylene chloride; Reaction Step b: sodium nitrite/hydrochloric acid/methanol/cuprous chloride; Reaction Step c: (i) aq. hydrochloric acid/methanol/reflux (ii) sodium hydroxide/sodium cyanide; Reaction Step d: conc. hydrochloric acid/reflux.; and Reaction Step e: di-tert.butyldicarbonate/-sodium hydroxide/tetrahydrofuran.

[0179] In Scheme 6, the procedure set forth in Scheme 4 is followed, but using

[0180] instead of

[0181] to obtain the corresponding urea (—C(O)NHR²⁰), amide (—C(O)CH₂R²⁰ or —C(O)R²⁰), sulfonamide (—SO₂R²⁰) or carbamate (—C(O)OR²⁰) products, wherein n is 0, can be prepared. Similarly, using

[0182] (obtained from XI following the procedures in Scheme 4), instead of

[0183] in Scheme 4 and 5 produces the corresponding ureas, amides, sulfonamides and carbamates wherein n is 0.

[0184] Those skilled in the art will appreciate that in Schemes 1, 2 and 4-6, other aldehydes can be used in place of

[0185] to obtain the other substituents for R⁸ in formula 1.0.

[0186] Those skilled in the art will also appreciate that using

[0187] instead of

[0188] in Schemes 4 and 5, and using instead of

[0189] in Scheme 6 will provide the corresponding compounds wherein the imidazole is bound to the alkyl chain by a ring carbon.

[0190] Reaction Scheme 7 (R⁹ and R¹⁰ Are Other Than H)

[0191] In Scheme 7, the alcohol 33.0 can be oxidized under standard conditions to give the aldehyde. Addition of the corresponding Grignard of R⁹ gives the alcohol which can be carried on to amine as in Scheme 1 or subject to reoxidation to the ketone followed by Grignard addition of R¹⁰. In the case where R⁹=R¹⁰, the ester 32.0 (Scheme 1) can be used as the electrophile with 2 equivalents of the appropriate Grignard reagent being added.

[0192] Reaction Scheme 8 (R⁹ and R¹⁰ Are Other Than H, C-Linked Imidazole)

[0193] In Scheme 8, the nitrile may be reduced with DIBAL-H to the aldehyde. Similar to the procedure in Scheme 7, the aldehyde can then be treated with the appropriate Grignard reagent to give the alcohol. There can be an additional round of oxidation and Grignard addition to give the R⁹, R¹⁰ disubstituted derivatives with either R⁹=R¹⁰ or R⁹·R¹⁰. The resulting alcohol may be converted to the amine by the methodology shown in either Schemes 1 or 2.

[0194] Compounds useful in this invention are exemplified by the following examples, which examples should not be construed as limiting the scope of the disclosure.

[0195] Ethyl 2,2-dimethyl acrylate (50.0 g, 2.0 eq.) was stirred with imidazole (13.28 g, 200 mmol) at 90° C. for 48 hours. The resulting solution was cooled, diluted with water (150 mL) and CH₂Cl₂ (150 mL) and separated. The aqueous layer was washed with CH₂Cl₂ (2×75 mL) and the combined organics were dried over NA₂SO₄ and concentrated in vacuo. The crude mixture was purified by flash chromatography using a 10% MeOH in CH₂Cl₂ solution as eluent to give the pure product as a clear oil (11.27 g, 29% yield). CIMS: MH⁺=197.

[0196] A solution of the title compound from Step A (10.0 g, 50.96 mmol) was treated with LiAlH₄ (51 mL, 1M solution in ether, 1.0 eq.). The reaction mixture was stirred one hour at room temperature before quenching by the dropwise addition of saturated Na₂SO₄ (˜3.0 mL). The resulting slurry was dried with Na₂SO₄ (solid), diluted with EtOAc (100 mL) and filtered through a plug of Celite. The filtrate was concentrated to give a yellow oil (6.87, 87% yield) which was used without further purification. CIMS: MH⁺=155.

[0197] To a solution of the title compound Step B (6.85 g, 44.42 mmol), phthalimide (7.19 g, 1.1 eq.), and Ph₃P (12.82 g, 1.1 eq.) in THF (200 mL) at 0° C. was added DEAD (7.69 mL, 1.1 eq.) over 10 minutes. The resulting solution was warmed to room temperature and stirred 48 hours. The reaction mixture was concentrated under reduced pressure and the product isolated by crystallization from CH₂Cl₂/Et₂O to give a white solid (10.03 g, 79% yield). CIMS: MH⁺=284

[0198] A solution of the title compound from Step C (9.50 g, 33.53 mmol) and N₂H₄ (1.25 mL, 1.2 eq.) in EtOH (100 mL) was heated at reflux 4 hours. The resulting slurry was cooled, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by flash chromatography using a 15% (10% NH₄OH in MeOH) solution in CH₂Cl₂ as eluent to give a pale yellow oil (2.80 g, 53% yield). LCMS: MH⁺=154

PREPARATIVE EXAMPLES 2-4

[0199] By essentially the same procedure as that set forth in Example 1, the amines in Column 3 of Table 1 were synthesized from the esters in Column 2. “No.” represents “Preparative Example Number”. TABLE 1 No. ESTER AMINE Mass Spec 2

CIMS: MH⁺ = 152 3

CIMS: MH⁺ = 236 4

MH⁺ = 168

[0200]

[0201] Piperazine anhydride (Preparative Example 44) (0.28 g, 1.0 eq.) was added portionwise to a solution of the title compound from Example 1 (0.17 g, 1.2 mmol) in CH₂Cl₂ (5.0 mL) and the resulting solution stirred 10 minutes at room temperature before adding cyclohexyl isocyanate (0.21 mL, 1.5 eq.). After stirring at room temperature 15 minutes, the reaction mixture was quenched by the addition of MeOH (1 mL), concentrated in vacuo, and purified by flash chromatography using a 10% MeOH in CH₂Cl₂ solution as eluent to yield a white solid (0.46 g, 85% yield). FABMS: MH⁺=491.

[0202] By the essentially the same procedure as that set forth in Preparative Example 5, except using ═N-(benzyloxycarbonyloxy)-succinimide (CBZ-OSuc) instead of cyclohexyl isocyanate, the title compound was prepared (0.16 g, 84% yield).

PREPARATIVE EXAMPLE 6.1

[0203] By essentially the same procedure as set forth in Preparative Example 6, except instead of the amine

[0204] use the amine from Preparative Example 2

[0205] to obtain

[0206] By essentially the same procedure as that set forth in Preparative Example 5, except using the title compound from Preparative Example 3 (Table 1), the title compound was prepared. LCMS: MH⁺=573.

[0207] Follow the same procedure as that set forth in Preparative Example 5, except use the amine from Preparative Example 2 to obtain the title compound.

[0208] Follow the same procedure as that set forth in Preparative Example 5, except use the amine from Preparative Example 4 to obtain the title compound.

[0209] Follow the same procedure as that set forth in Preparative Example 5, except use the amine from Preparative Example 10 to obtain the title compound.

PREPARATIVE EXAMPLE 8

[0210]

[0211] To the title compound from Preparative Example 1, Step D, (0.82 g, 5.35 mmol) in CH₂Cl₂ (10 mL) and TEA (0.75 mL, 1.0 eq) was added piperazine anhydride (1.65 g, 1.2 eq.) (prepared as described in Preparative Example 44) portionwise and the resulting solution was stirred at room temperature. When the reaction was complete (TLC), the solution was concentrated in vacuo and the crude product was purified by flash chromatography using a 10% (10% NH₄OH in MeOH) in CH₂Cl₂ then 20% (10% NH₄OH in MeOH) in CH₂Cl₂ as eluent. CIMS: MH⁺=366.

[0212] The title compound from Step A was stirred at room temperature in a 50% solution of TFA in CH₂Cl₂ (25 mL) for 2 hours. The resulting solution was concentrated under reduced pressure. Any residual TFA was removed by azeotroping with toluene to give the crude product which was used without further purification. CIMS: MH⁺=266.

[0213] The title compound from Step B was dissolved in CH₂Cl₂ (30 mL) and TEA (7.62 mL, 10 eq.) was added. The reaction mixture was stirred 5 minutes before adding chloride

[0214] (0.908 g, 0.5 eq.). The resulting solution was stirred at room temperature for 96 hours. The reaction mixture was diluted with water (50 mL), separated and the aqueous layer extracted with CH₂Cl₂ (2×200 mL). The combined organics were dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 5%, 7.5%, and then 10% (10% NH₄OH in MeOH) in CH₂Cl₂ solution as eluent (0.926 g, 30% yield). CIMS: MH⁺=571.

[0215] The title compound from Step C was separated into individual diasteromers by Preparative HPLC using a ChiralPak AD column using a 20% IPA in hexanes with 0.2% diethylamine solution as eluent:

[0216] Isomer A (11S,2R(−)-Isomer): retention time=18.2 minutes; [α]²⁰ _(D)=−31.7 (3.0 mg in 2.0 mL MeOH).

[0217] Isomer B (11R,2R(−)-Isomer): retention time=30.3 minutes; [α]²⁰ _(D)=−6.2 (2.4 mg in 2.0 mL MeOH).

[0218] By essentially the same procedure as described in Preparative Example 8, except using the title compound from Preparative Example 2 (Table 1), the title compound was prepared.

[0219] The 11(S)- and 11(R)-isomers

[0220] were separated by Preparative HPLC using a CHIRALPAK AD column using a 30% IPA in hexanes containing 0.2% diethylamine solution as eluent.

[0221] 11S,2R(−)-isomer: retention time=10.2 minutes; MH⁺=569; [∝]²⁰ _(D)=−32.7 (4.04 mg in 2.0 mL MeOH).

[0222] 11R,2R(−)-isomer: retention time=22.8 minutes; MH⁺=569; [∝]²⁰ _(D)=−1.2 (3.40 mg in 2.0 mL MeOH).

PREPARATIVE EXAMPLE 9.1

[0223] Follow the procedure set forth in Preparative Example 8, except use the amine

[0224] in Step A instead of

[0225] and use the 10-Cl tricycle chloride

[0226] in Step C instead of the 3-Br-8-Cl-tricycle chloride (Compound 42.0) to obtain the compounds

[0227] Obtain the 10-Cl tricycle chloride (10,11-diChloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-B]pyridine) as follows:

[0228] The ketone (starting material) 5,6-dihydro-10-Chloro-11H-benzo[5,6]cyclohepta[1,2-c]pyridine-11-one, can be prepared following the procedure described by Villani et al., J. Het. Chem. 8, 73-81 (1971). The product was prepared substituting the 10-Chloro for the 10H tricycle and following the procedure described in Preparative Example 169.

[0229] 1H NMR (CDCl₃ δ) 2.97 (m, 2H), 3.55 (m, 1H), 4.03 (m, 1H), 7.11 (s,1H), 7.13 (d, 1H), 7.22 (m, 2H), 7.31 (d, 1H), 7.53 (d, 1H), 8.49 (d, 1H).

[0230] Imidazole (2.73 g, 40.1 mmol) in crotonitrile (10 mL) was heated to reflux overnight. The resulting solution was concentrated in vacuo, the residue diluted with Et₂O (50 mL) and washed with water (2×100 mL) and brine (1×25 mL). The combined organics were dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 15% MeOH in CH₂Cl₂ solution as eluent (2.13 g, 39% yield). FABMS: MH⁺=136.

[0231] A solution of the title compound from Step A (0.50 g, 0.0037 mmol) in THF (10 mL) was treated with LAH (5.5 mL, 1.0 M in Et₂O, 1.1 eq.). The reaction mixture was stirred at room temperature 3 hours and quenched by the dropwise addition of saturated Na₂SO₄. The resulting slurry was dried by the addition of solid NA₂SO₄ and filtered through a plug of Celite. The filtrate was concentrated under reduced pressure and the crude residue purified by flash chromatography using a 20% (10% NH₄OH in MeOH) solution as eluent (0.03 g, 6% yield).

[0232] nBuLi (2.5 mL; 2.5M in hexanes; 2.1 eq.) was added to iPr₂NH (0.87 mL, 2.1 eq.) in THF (8.0 mL) at 0° C. The resulting solution was stirred 45 minutes before adding the nitrile (1.0 g, 2.97 mmol) in THF (7.0 mL). The reaction mixture was stirred at 0° C. for 30 minutes before adding MeI (0.37 mL, 2.0 eq.). The resulting solution was warmed to room temperature and stirred one hour. The reaction was quenched by the addition of 1N HCl until acidic, diluted with water (40 mL) and extracted with EtOAc (2×200 mL). The combined organics were dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 40% EtOAc solution in hexanes as eluent (0.37 g, 33% yield). MH⁺=378.

[0233] LiAlH₄ (2.7 mL; 1.0 M solution in THF; 1.5 eq.) was added to the title compound from Step A (0.68 g, 1.80 mmol) in THF (5.0 mL). The resulting solution was stirred at room temperature 1.5 hours and quenched by the dropwise addition of saturated Na₂SO₄ (10 mL). The solution was extracted with Et₂O (2×200 mL), the combined organics dried over MgSO₄ and concentrated under reduced pressure (0.6 g, 88% yield).

[0234] following the same procedure as set forth in Preparative Example 27 Step C, the title compound was prepared.

[0235] A solution of the piperazine carboxylic acid (0.29 g, 0.881 mmol) prepared as described in Preparative Example 43, L-histidinamide dihydrochloride (0.20 g, 1.0 eq.), DEC (0.25 g, 1.5 eq.), HOBT (0.18 g, 1.5 eq.), and NMM (0.48 mL, 1.5 eq.) in DMF (5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water (25 mL) and CH₂Cl₂ (50 mL), separated, and the aqueous layer extracted with CH₂Cl₂ (2×50 mL). The combined organics were dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 15% MeOH in CH₂Cl₂ solution as eluent (0.24 g, 59% yield). FABMS: MH⁺=467.

PREPARATIVE EXAMPLES 13-17

[0236] Following the procedures found in J. Chem. Soc. Perkin I (1979), 1341-1344, the following N-substituted histamines were prepared:

PREPARATIVE EXAMPLES 18-26

[0237] By essentially the same procedure as that set forth in Preparative Example 74, and using the aldehydes and amines set forth in Table 2, one can obtain the intermediate products shown in Table 2. TABLE 2 Prep Ex. Aldehyde Amine Product 18

19

20

21

22

23

24

25

26

[0238]

[0239] Dissolve the nitrile (1.5 g, 4.29 mmol) in 10 mL of THF and cool to −78° C. under nitrogen. Add 20 mL of a 1.5 M LDA solution (in cyclohexane). Then add dropwise over 2 hr. a solution of 790 mg (4.293 mmol) of 2-methylpropyliodide in 10 mL of THF. Allow to warm to room temperature and stir overnight. Add 10 mL of water followed by 1N HCl until pH of 10-11. Dilute with 100 mL of methylene chloride followed by 20 mL of sat. aqueous Na₂SO₄. Add MgSO₄ until solution is clear. Separate the organic layer and dry over MgSO₄. Concentrate under vacuum and flash chromatograph on silica gel using ethyl acetate-hexane (1-3) to give the product as a tan semi-solid.

[0240] Dissolve the product of Step A (0.5 g, 1.23 mmol) in 10 mL of ethanol saturated with ammonia. Add 8.8 mg (0.017 mmol) of H₂PtCl₆.6H₂O, 1 g of Raney Ni in water and hydrogenate at 54 psi on a Parr shaker over night. Filter through Celite and concentrate under vacuum.

[0241] Dissolve the product of Step B (0.165 g, 0.403 mmol) in 4 mL of 2M HCl and 2 mL of methanol. Reflux for 100 min. then concentrate under vacuum. Triturate the residue with ether to give the product hydrochloride as a white solid.

PREPARATIVE EXAMPLES 28-29, 29.1 and 30

[0242] Following the procedure set forth in Preparative Example 27, but using the indicated alkyl or benzyl halide in place of 2-methyl propyl iodide, the substituted histamines shown were prepared.

[0243] Ethyl 4-pyridyl acetate (4.5 g, 27.24 mmoles) was placed in a 500 mL Parr bottle and dissolved in anhydrous EtOH (70 mL). To the bottle was added 10% Palladium on charcoal (1.0 g). The bottle was put on a hydrogenator and the contents shaken under 55 psi hydrogen pressure at 25° C. for 94 h. The mixture was filtered through Celite® and washed with 4×40 mL anhydrous EtOH. The filtrate was rotovapped down and the residue chromatographed on silica gel using 3% (10% conc. NH₄OH in methanol)dichloromethane as the eluant to give the title compound (Yield: 2.944 g, 63%): FABMS: m/z 172.2(MH⁺); δ_(C) (CDCl₃) CH₃: 14.3; CH₂: 33.2, 33.2, 41.9, 46.5, 46.5 60.2; CH: 33.4; C: 172.7; δ_(H) (CDCl₃) 1.18 (m,1H,H₄), 1.26 (t,3H,CH₃), 1.71(2H), 1.90(1H), 1.96(1H), 2.22(d,2H), 2.63(2H), 3.07(2H), 4.13(q.2H,CH₃ CH₂ —).

[0244] Ethyl 4-piperidinyl acetate from Preparative Example 31 (500 mg; 2.92 mmoles) was dissolved in anhydrous CH₂Cl₂ (25 mL). To the stirring solution was added trimethylsilyl isocyanate (5.9 mL; 43.8 mmoles) and the solution was stirred at 25° C. for 17 h. The solution was worked up in CH₂Cl₂-saturated NaHCO₃ and the product chromatographed on silica gel using 2→3% (conc. NH₄OH in methanol)dichloro-methane as the eluant to give the title compound (Yield: 622 mg, 99%): CIMS: m/z 215.3 (MH⁺); δ_(C) (CDCl₃): CH₃: 14.2; CH₂: 31.6, 31.6, 41.0, 44.2, 44.2, 60.4; CH: 32.9; C: 158.2, 172.4; δ_(H) (CDCl₃): 1.23 (m,1H,H₄), 1.27 (t,3H,CH₃), 1.75 (d,2H), 1.98 (m,1H), 2.26 (d,2H), 2.85 (t,2H), 3.94 (d, 2H), 4.15 (q,2H,CH₃ CH₂ —), 4.56 (bs,2H).

[0245] Ethyl 1-aminocarbonyl-4-piperidinyl acetate from Preparative Example 32 (153.6 mg, 0.717 mmoles) was dissolved in anhydrous CH₂Cl₂ (3.58 mL) and EtOH (3.58 mL). To the solution was added 1.0M LiOH (1.73 mL, 1.73 mmoles) and the mixture was stirred at 50° C. for 5.5 h. The mixture was cooled quickly to 25° C. and 1.0N HCl (2.02 mL, 2.02 mmoles) was added and the mixture stirred for 5 minutes and then rotovapped to dryness to give the title compound which was used without further purification.

[0246] The C₁₁-racemate of the above isomers (Preparative Example 141) (62% pure) was subjected to preparative HPLC on a Chiralpak AD® column (50×5 cm) using 75% hexane-25% isopropyl alcohol-0.2% diethylamine as the eluant to give, in the order of elution, the 11-S(−)-isomer and the 11-R(−)-isomer.

[0247] 11S,2R(−)-isomer: (Yield: 0.8756 g, 55%): LCMS: m/z 543.1 (MH⁺); δ_(C) (CDCl₃) CH₂: 30.3, 30.4, 31.0, 36.3, 44.3, 44.7, 52.0, 54.5; CH: 58.7, 79.4, 118.8, 126.0, 129.6, 130.4, 132.3, 137.1, 141.3, 147.0; C: 120.0, 134.0, 135.4, 136.7, 140.9, 155.4, 172.2; δ_(H) (CDCl₃) 2.02 (2H, m, 2″—CH₂), 3.32 (2H, m, 3″—CH₂), 3.98 (2H, dd, 1″—CH₂), 4.30 (1H, s, H₁₁), 6.93 (1H, s, Im-H₅), 6.97 (1H, t, CONHCH₂), 7.06 (1H, s, Im-H₄), 7.11 (1H, s, Ar—H), 7.13 (2H, s, Ar—H), 7.16 (1H, s, Ar—H), 7.49 (1H, s, Ar—H₁₀), 7.57 (1H, d, Im-H₂) and 8.33 ppm (1H, s, Ar—H₂); [a]_(D) ^(20° C.) −45.0° (MeOH, c=9.32 mg/2 mL).

[0248] 11R,2R(−)-isomer: (Yield: 0.5979 g, 38%): LCMS: m/z 543.1 (MH⁺); δ_(C) (CDCl₃) CH₂: 30.2, 30.3, 31.1, 36.4, 44.1, 44.7, 52.2, 54.0; CH: 58.2, 79.4, 118.8, 126.1, 129.6, 130.7, 132.3, 137.0, 141.2, 146.8; C: 119.9, 134.0, 135.2, 136.9, 140.7, 155.7, 172. 1; δ_(H) (CDCl₃) 3.34 (2H, m, 3″—CH,), 3.97 (2H, dd, 1″—CH₂), 4.30 (1H, s, H₁₁), 6.93 (1H, s, Im-H₅), 7.06 (1H, s, Im-H₄), 7.08 (1H, s, Ar—H), 7.11 (2H, s, Ar—H), 7.14 (1H, s, Ar—H), 7.15 (1H, t, CONHCH₂), 7.50 (1H, s, Ar—H₁₀), 7.58 (1H, d, Im-H₂) and 8.35 ppm (1H, s, Ar—H₂); [a]_(D) ^(23 5° C.) −12.0° (MeOH, c=10.19 mg/2 mL).

[0249] Isonipecotic acid (10 g, 77.42 mmoles) and sodium hydroxide (3.097 g, 77.42 mmoles) were dissolved in THF-water (1:1) (230 mL) and di-t-butyldicarbonate (18.59 mL, 85.177 mmoles) was added. The solution was stirred at 25° C. for 90 h. The mixture was treated with BioRad® 50W-X4(H⁺) ion exchange resin (86.6 mL) and the resin was filtered off and washed with THF and then water. The combined filtrates were evaporated to dryness to give the title compound which was used without further purification in the next step: FABMS: m/z 229.9 (MH⁺); δ_(C) (d₆-DMSO) CH₃: 28.0, 28.0, 28.0; CH₂: 42.0-43.1(broad signal); CH: obscured; C: 78.5, 153.8, 175.6.

[0250] The title compound from Step A above (2 g, 8.72 mmoles) was dissolved in dry DMF (40 mL) and the solution was stirred at 0° C. under an argon atmosphere. Diphenylphosphoryl azide (2.07 mL, 9.59 mmoles) was added over 10 min followed by triethylamine (2.68 mL, 9.59 mmoles) and the mixture was stirred at 0° C. for 1 h and then at 25° C. for 19 h. Evaporation to dryness followed by chromatography on a silica gel column using 5% increasing to 7% methanol in dichloromethane afforded the title compound: (Yield: 1.57 g, 72%): δ_(C) (CDCl₃) CH₃: 28.5, 28.5, 28.5; CH₂: 32.9 (broad), 42.8 (broad); CH: 47.3; C: 79.7, 154.8, 156.5.

[0251] Method 1

[0252] 4-Hydroxypiperidine (5 g, 49.43 mmoles) was dissolved in anhydrous dichloromethane (50 mL) and trimethylsilyl isocyanate (6.27 g, 7.36 mL, 54.38 mmoles) was added. The mixture was stirred at 25° C. under an argon atmosphere for 24 h. Water (10 mL) was added and the mixture was evaporated to dryness. The residue was chromatographed on a silica gel column using 10% (10% conc. NH₄OH in methanol)-dichloromethane as the eluent to give the title compound: (Yield: 6.895 g, 97%): CIMS: m/z 145.1 (MH⁺); δ_(C) (d₆-DMSO) CH₂: 34.2, 34.2, 41.3, 41.3; CH: 66.1; C: 158.0; δ_(H) (d₆-DMSO) 1.22 (2H, m, 3/5-CH₂), 1.68 (2H, m, 3/5-CH₂), 2.84 (2H, m, 2/6-CH₂), 3.60 (1H, m, 4-CH), 3.68 (2H, m, 2/6-CH₂), 4.67 (1H, d, OH) and 5.87 ppm (2H, s, NH₂).

[0253] Method 2

[0254] 4-Hydroxypiperidine (10 g, 98.86 mmoles) and urea (59.4 g, 988.6 mmoles) were dissolved in distilled water (100 mL) and the solution was heated at 100° C. for 67 h. The solution was evaporated to dryness and the product was chromatographed on a silica gel column using 10% (10% conc. NH₄OH in methanol)-dichloromethane as the eluent to give the title compound: (Yield: 8.3 g, 58%).

[0255] The title compound from Step A above (1 g, 6.94 mmoles) and 4-nitrophenyl chloroformate (1.54 g, 7.63 mmoles) were dissolved in anhydrous pyridine (10 mL) and the mixture was stirred at 25° C. for 24 h. The mixture was evaporated to dryness and the residue was azeotroped with toluene. The resulting product was chromatographed on a silica gel column using 3% methanol in dichloromethane as the eluant to give the title compound: (1.35 g, 63%): CIMS: m/z 310.05 (MH⁺); δ_(C) (CDCl₃) CH₂: 29.9, 29.9, 40.7, 40.7; CH: 74.9, 121.7, 121.7, 125.2, 125.2; C: 145.2, 151.7, 155.3, 158.7; δ_(H) (CDCl₃) 1.82 (2H, m, 3/5-CH₂), 2.01 (2H, m, 3/5-CH₂), 3.06 (2H, s, NH₂), 3.31 (2H, m, 2/6-CH₂), 3.68 (2H, m, 2/6-CH₂), 4.98 (1H, m, 4-CH), 7.39 (2H, d, Ar—H1/6) and 8.28 ppm (2H, d, Ar—H3/5).

[0256] The anhydride (0.5088 g, 1.99 mmoles) (prepared as described in Preparative Example 44) and 1-(3-aminopropyl)-imidazole (0.260 mL, 2.18 mmoles) were dissolved in anhydrous dichloromethane (10 mL) and the mixture was stirred under argon at 25° C. for 5 min. The mixture was diluted with dichloromethane and extracted with saturated aqueous sodium bicarbonate. The dichloromethane layer was dried (MgSO₄), filtered and evaporated to dryness. The resulting product was chromatographed on a silica gel column using 10% (conc, NH₄OH in methanol)-dichloromethane as the eluent to give the title compound: (Yield: 0.4955 g, 74%); LCMS: m/z 338.1 (MH⁺); δ_(C) (CDCl₃) CH₃: 28.4, 28.4, 28.4; CH₂: 31.1, 36.5, ˜43.5(broad), 44.8, ˜46.5(broad),; CH: 58.2, ˜119.0(broad), ˜129.7(broad), ˜137.3(broad); C: 80.2, 154.7, 171.5; δ_(H) (CDCl₃) 1.47 (9H, s, CH₃), 6.96 (1H, s, Im-H₅), 7.08 (1H, s, Im-H₄) and 7.52 ppm (1H, s, Im-H₂).

[0257] The title compound from Step A above (0.3248 g, 0.96 mmoles), 4-pyridylacetic acid N1-oxide (0.1916 g, 1.25 mmoles), 1 [3-(dimethylamino)propyl]-3-ethylcarbodimide hydrochloride (0.24 g, 1.25 mmoles), 1-hydroxybenzotriazole (0.169 g, 1.25 mmoles) and 4-methylmorpholine (0.1376 mL, 1.25 mmoles) were dissolved in anhydrous DMF (11 mL) and the mixture was stirred under argon at 25° C. for 18 h. The mixture was evaporated to dryness and the residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO₄), filtered and evaporated to dryness. The product was chromatographed on a silica gel column using 5% (10% conc. NH₄OH in methanol)-dichloromethane as the eluant to give the title compound: (Yield: 0.4333 g, 95%); LCMS: m/z 473.1 (MH⁺); δ_(C) (CDCl₃) CH₃: 28.3, 28.3, 28.3; CH₂: 30.8, 36.5, 38.7, 43.2, ˜43.5 (broad), ˜44.5 (broad); CH: 53.8, ˜119.2 (broad), 127.4, 127.6, ˜129.3 (broad), ˜137.5 (broad), 138.7, 138.9; C: 80.7, 134.5, 154.4, 169.6, 169.6; δ_(H) (CDCl₃) 1.44 (9H, s, CH₃), 6.97 (1H, broad s, Im-H₅), 7.09 (1H, broad s, Im-H₄), 7.20 (2H, m, Ar—H), 7.53 (1H, broad s, Im-H₂) and 8.14 ppm (2H, d, Ar—H).

[0258] The title compound from Step B above (0.289 g, 0.612 mmoles) was dissolved in anhydrous dichloromethane (7.8 mL) and trifluoroacetic acid (2.026 mL, 26.3 mmoles) was added. The mixture was stirred at 25° C. for 1.25 h under argon and then evaporated to dryness. The product was chromatographed on a silica gel column using 5% increasing to 10% (10% conc. NH₄OH in methanol)-dichloromethane as the eluant to give the title compound: (Yield: 0.208 g, 91%); LCMS: m/z 373.1 (MH⁺); δ_(C) (CDCl₃—CD₃OD) CH₂: 30.4, 36.2, 38.2, 43.9, 44.5, 46.2, 46.7; CH: 52.3, ˜119.2 (broad), 127.7, 127.7, ˜128.3 (broad), 137.4 (broad), 138.4, 138.5, 138.5; C: 137.3, 169.8, 170.6; δ_(H) (CDCl₃—CD₃OD) 6.90 (1H, broad s, Im-H₅), 6.94 (1H, broad s, Im-H₄), 7.22 (2H, m, Ar—H), 7.47 (1H, broad s, Im-H₂) and 8.12 ppm (2H, d, Ar—H); [α]_(D) ^(26.3°)+81.1° (c=10.43 mg/2 mL, methanol).

[0259] To a solution of 3-bromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (2 g) (6.2mmoles) in anhydrous dichloromethane (14 ml) at 0° C. and under an argon atmosphere, was added a solution of 3-chloroperbenzoic acid (1.76 g) (10.4 mmoles) in anhydrous dichloromethane (35 ml) dropwise over a period of 30 minutes. The mixture was allowed to warm to room temperature and after 18 h additional 3-chloro-perbenzoic acid (0.88 g) (5.2 mmoles) in anhydrous dichloro-methane (25 ml) was added and the mixture was stirred for a total of 42 h. The mixture was diluted with dichloromethane and washed with 1N NaOH (200 ml). The aqueous layer was extracted with additional dichloromethane (2×200 ml) and the combined organic layers were dried over magnesium sulfate, filtered and evaporated to dryness. The product was chromatographed on silica gel using 0.25%-0.5%-1% (10% conc. NH₄OH in methanol)dichloromethane as the eluant to give the title compound (Yield: 1.386 g, 66%): ESIMS; m/z 338.1 (MH⁺); δ_(C) (CDCl₃) CH₂: 30.5, 34.0; CH: 126.9, 127.6, 130.3, 132.5, 140.4; C: 121.0, 135.1, 138.3, 139.7, 141.6, 145.3, 188.0 ppm.

[0260]

[0261] The title compound of Step A (1.3422 g) (3.96 mmoles) was dissolved in methanol (18 ml) and dichloromethane (20 ml) and sodium borohydride (0.219 g) (5.79 mmoles) was added. The mixture was stirred under argon at 0° C. for 1 h and then allowed to warm up to 25° C. over a period of 1 h. The mixture was diluted with dichloromethane (800 ml) and washed with 1N NaOH (150 mL). The aqueous layer was extracted with dichloromethane (2×100 ml) and the combined organic layers were dried over magnesium sulfate, filtered and evaporated to dryness. The product was chromatographed on silica gel using 1% (10% conc. NH₄OH in methanol)dichloro-methane as the eluant to give the title compound (Yield: 1.24 g, 92%): ESIMS: m/z 340.1 (MH⁺); δ_(C) (CDCl₃) CH₂: 31.2, 32.0; CH: 69.1, 126.8, 129.5, 131.7, 131.7, 136.7; C: 118.3, 134.7, 135.2, 139.7, 141.0, 148.9 ppm.

[0262] The title compound from Step B (0.552 g, 1.62 mmoles) and triethylamine (1.19 mL, 8.52 mmoles) were dissolved in anhydrous dichloromethane (8.5 mL) and the solution was cooled to 0° C. Methanesulfonyl chloride (0.4 mL, 5.166 mmoles) was added over 30 min and the mixture was stirred at 0° C. for a total of 1.25 h. The solution was evaporated to dryness to give the 11-mesyl derivative which was used without further purification. The latter was dissolved in anhydrous dichloromethane (40 mL) and the solution was stirred at 0° C. N-[3-(1H-Imidazol-1-yl)propyl]-2(R)-piperazinecarboxamide (Preparative Example 136) (0.5 g, 2.11 mmoles) dissolved in anhydrous dichloromethane (20 mL) and anhydrous DMF (20 mL) was added at 0° C. and the solution was stirred and allowed to warm up to 25° C. over 2 h. The reaction was allowed to proceed at 25° C. for 18 h and was then diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate, dried (MgSO₄), filtered and evaporated to dryness. The product was chromatographed on a silica gel column using 4% (10% conc. NH₄OH in methanol)-dichloro-methane as the eluant to give the title racemic compound: Yield: 0.399 g, 44%); FABMS: m/z 559.3 (MH⁺).

[0263] The title racemic compound from Step C above (0.395 g) was subjected to preparative HPLC on a Chiralpak AD® column (50×5 cm) using 65% hexane-35% isopropyl alcohol-0.2% diethylamine as the eluant to give in the order of elution the 11-R(+)-diastereoisomer of the title compound followed by the 11-S(−)-diastereoisomer of the title compound.

[0264] 11R,2R(+)-diastereoisomer: (Yield: 0.1854 g); FABMS: m/z 559.2 (MH⁺); δ_(C) (CDCl₃) CH₂: 30.1, 30.3, 31.2, 36.4, 43.9, 44.7, 51.6, 52.8; CH: 57.8, 64.3, 118.9, 126.3, 129.6, 130.6, 130.7, 133.4, 137.3, 138.4; C: 118.2, 133.6, 134.6, 140.1, 141.0, 148.1, 172.0; δ_(H) (CDCl₃) 5.70 (1H, s, H₁₁), 6.95 (1H, broad s, Im-H,), 7.04 (1H, broad s, Im-H₄), 7.51 (1H, broad s, Im-H₂) and 8.22 ppm (1H, s, Ar—H₂); [a];_(D) ^(20°)+41.2° (c=11.08 mg/2 mL. methanol).

[0265] 11S,2R(−)-diastereoisomer: (Yield: 0.18 g); FABMS: m/z 559.2 (MH⁺); δ_(C) (CDCl₃) CH₂: 30.1, 30.3, 31.1, 36.5, 44.4, 44.8, 51.6, 53.4; CH: 58.9, 64.4, ˜119.2, 126.3, 129.5, 130.6, 130.7, 133.4, ˜137.3, 138.5; C: 118.3, 133.7, 134.6, 139.9, 141.0, 148.1, 172.1; δ_(H) (CDCl₃) 5.69 (1H, s, H₁₁), 6.94 (1H, broad s, Im-H₅), 7.07 (1H, broad s, Im-H₄), 7.51 (1H, broad s, Im-H₂) and 8.26 ppm (1H, s, Ar—H₂); [a]_(D) ^(19 9°−71.0)° (c=10.32 mg/2 mL, methanol).

[0266] Ethyl 4-pyridyl acetate (4.5 g, 27.24 mmoles) was placed in a 500 mL Parr bottle and dissolved in anhydrous EtOH (70 mL). 10% Palladium on charcoal (1.0 g) was added and the contents shaken under 55 psi hydrogen pressure at 25° C. for 94 h. The mixture was filtered through Celite® and washed with 4×40 mL anhydrous EtOH. The filtrate was evaporated to dryness and the residue was chromatographed on silica gel using 3% (10% conc. NH₄OH in methanol)-dichloromethane as the eluant to give the title compound: (Yield: 2.944 g, 63%): FABMS: m/z 172.2 (MH⁺); δC (CDCl₃) CH₃: 14.3; CH₂: 33.2, 33.2, 41.9, 46.5, 46.5 60.2; CH: 33.4; C: 172.7; δH (CDCl₃) 1.18 (1H, m, H₄), 1.26 (3H, t,CH₃), 1.71(2H), 1.90(1H), 1.96(1H), 2.22(2H, d), 2.63(2H), 3.07(2H), 4.13 ppm (2H, q, CH₃ CH₂ —).

[0267] Ethyl 4-piperidinyl acetate (500 mg; 2.92 mmoles) from Step A above was dissolved in anhydrous dichloromethane (25 mL). To the stirred solution was added trimethylsilyl isocyanate (5.9 mL; 43.8 mmoles) and the solution was stirred at 25° C. for 17 h. The solution was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The dichloromethane layer was dried (MgSO₄), filtered and evaporated to dryness. The product was chromatographed on silica gel using 2% increasing to 3% (10% conc. NH₄OH in methanol)-dichloromethane as the eluant to give the title compound: (Yield: 622 mg, 99%): CIMS: m/z 215.3 (MH⁺); δ_(C) (CDCl₃): CH₃: 14.2; CH₂: 31.6, 31.6, 41.0, 44.2, 44.2, 60.4; CH: 32.9; C: 158.2, 172.4; δ_(H) (CDCl₃): 1.23 (1H, m, H₄), 1.27 (3H, t, CH₃), 1.75 (2H, d), 1.98 (1H, m), 2.26 (2H, d), 2.85 (2H, t), 3.94 (2H, d), 4.15 (2H, q, CH₃ CH₂ —), 4.56 (2H, bs).

[0268] Ethyl 1-aminocarbonyl-4-piperidinyl acetate (153.6 mg, 0.717 mmoles) from Step B above was dissolved in anhydrous dichloromethane (3.58 mL) and ethanol (3.58 mL). To the solution was added 1.0M LiOH (1.73 mL, 1.73 mmoles) and the mixture was stirred at 50° C. for 5.5 h. The mixture was cooled quickly to 25° C. and 1.0N HCl (2.02 mL, 2.02 mmoles) was added and the mixture stirred for 5 minutes and then evaporated to dryness to give the title compound, which was used without further purification.

[0269] The title compound from Preparative Example 37, Step A above (0.45 g, 1.33 mmoles), 1 [3-(dimethylamino)propyl]-3-ethylcarbodimide hydrochloride (0.332 g, 1.73 mmoles), 1-hydroxybenzotriazole (0.234 g, 1.73 mmoles) and 4-methyl-morpholine (0.382 mL, 3.46 mmoles) were dissolved in anhydrous DMF (7 mL). The title compound from Preparative Example 33, Step C above (0.3228 g, 1.73 mmoles) dissolved in anhydrous DMF (8 mL) was added and the mixture was stirred at 25° C. for 22 h. The solution was evaporated to dryness and the residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate, dried (MgSO₄), filtered and evaporated to dryness. The residue was chromatographed on a silica gel column using 5% (10% conc. NH₄OH in methanol)-dichloromethane as the eluant to give the title compound: (Yield: 0.3553 g, 53%).

[0270] The title compound from Step A above (0.45 g, 0.9 mmoles) was dissolved in methanol (5.625 mL). A 10% (v/v) solution of conc. H₂SO₄ in dioxane (13.5 mL) was added and the mixture was stirred at 25° C. for 2 h. Anhydrous methanol (200 mL) was added followed by BioRad® AG1-X8 (OH⁻) resin until the solution was neutral to pH paper. The resin was filtered off and washed with methanol and the combined filtrates were evaporated to dryness. The residue was chromatographed on a silica gel column using 5% increasing to 6.5% (10% conc. NH₄OH in methanol)dichloro-methane as the eluant to give the title compound: (Yield: 0.317 g, 96%); FABMS: m/z 406.2 (MH⁺); δ_(C) (CDCl₃-˜5% CD₃OD) CH₂: 30.8, 31.9, 31.9, 36.2/36.3/36.6, 39.1/39.3/39.5, 44.1/44.2, 44.4, 44.4, 44.8, 44.8; CH: 51.2/56.3, 119.0, 128.8, 137.0; C: 158.7, 171.0/171.1, 171.9/172.6; δ_(H) (CDCl₃-2.86% CD₃OD) 4.84 (1H, d, H₂), 6.96 (1H, broad s, Im-H₅), 7.04 (1H, broad s, Im-H₄) and 7.53 ppm (1H, broad s, Im-H₂).

[0271] A solution of 52.i (J. Med. Chem. 4890-4902 (1988))(205 g) in conc. HCl (1 L) and water (100 mL) is refluxed for 18 h, then poured into ice (3 Kg). Aq. 50% NaOH is added to pH 12 followed by extraction with EtOAc (3×4 L), the extracts are washed with brine, dried and evaporated to afford 52.ii (166 g).

[0272] A 1M solution of DIBAL in toluene (908 mL) is added dropwise during 2 h to a solution of 52.ii (166 g) in toluene (4 L) at rt. followed by stirring for 18 h. The mixture is cooled to 0-5° C. and stirred for 1 h and extracted with 1N HCl (2 L). The aqueous extract is basified to pH 10 with 50% NaOH and extracted with EtOAc (3×2 L). The extracts are evaporated and chromatographed on silica-gel (1 Kg). Elution with 10% MeOH/CH₂Cl₂ affords the title compound (±) 52.0 (104 g): HRMS (FAB) calcd for C₁₉H₂₁N₂ ⁷⁹BrCl 393.0556, found 393.0554.

[0273] Step C

[0274] The racemate (±) 52.0 (96 g) is resolved by HPLC on a 8×30 cm CHIRALPAK AD column at 25° C. with the UVdetector set at 290 nm. Elution with 0.05% diethylamine-methanol affords: Peak 1 (−) 52.0 (40 g): [α]_(D) ²⁰−28.4° (c 0.3, MeOH); Further elution with the same solvent affords: Peak 2 (+) 52.0 (42 g): [α]_(D) ²⁰+27.5° (c 0.3, MeOH).

[0275] A solution of (+)-52.0 (2.3 g) in dimethylformamide (30 ml) is reacted with isatoic anhydride (1.25 g) in the presence of DMAP (0.1 g) at r.t. for 3 hrs and is then evaporated under reduced pressure and residual dimethylformamide is azeotroped with toluene. The residue is dissolved in ethylacetate (50 ml) and the solution is extracted with 10% sodium carbonate (3×100 ml). The organic layer is filtered through silica-gel (100 ml) followed by elution with ethylacetate. The filtrate is evaporated under reduced pressure to afford the title compound 53.0 as an amorphous solid (3.68 g). MS(FAB): m/z 510 (MH)⁺.

[0276] A solution of 53.0 (3.1 g) and sodium nitrite (0.8 g) in methanol (500 ml) is stirred at r.t. under nitrogen with cuprous chloride (0.15 g) while adding dropwise over 10 minutes a 4M hydrochloric acid/dioxane solution (3.9 ml). The reaction mixture is stirred for 24 hrs followed by the addition of 10% sodium carbonate to pH 8, concentrated under reduced pressure, diluted with water (200 ml) and extracted with dichloromethane (4×100 ml). The combined extract is evaporated under reduced pressure and the crude reaction product is flash chromatographed on silica-gel (400 ml). Elution with 25% ethylacetate-hexane affords after evaporation the title compound 54.0a and 54.0b as an off-white amorphous solid (2.97 g). ¹H NMR (CDCl₃, 300 MHz) d 3.30 (s, 3H); MS (FAB) m/e 525 (MH)⁺.

[0277] A solution of 54.0a and 54.0b (17 g) in methanol (150 ml) and 2N hydrochloric acid (170 ml) and conc. HCl (60 ml) is heated under reflux for 17 hrs, followed by evaporation under reduced pressure. The resulting amorphous solid is dissolved in methanol (160 ml) and sodium cyanide (15 g) is added with stirring until the reaction is basic (pH 8). The reaction is stirred for 2 h, diluted with dichloromethane (300 ml) and filtered. The filtrate is evaporated and the residue is dissolved in conc HCl (150 ml) and the mixture is heated in an oil bath (120° C.) for 4 h and is then evaporated under reduced pressure. The residue is dissolved in THF (100 ml) and 10% NaOH (30 ml) is added to pH>8 followed by the dropwise addition of a solution of (BOC)₂O (9 g) in THF (50 ml) with vigorous stirring for 24 h. The solution is concentrated to a low volume, stirred with hexane (2×120 ml) and ice-water followed by acidification of the aqueous layer with citric acid and extraction with EtOAc. The crude product obtained by evaporating the extract is purified by flash chromatography to afford the mixture of 57.0a and 57.0b as light tan solid that appears as a single tic spot (16 g). ¹H NMR (CDCl₃, 300 MHz) d 1.40 (s, 9H); MS (FAB) m/z 535 (MH)⁺.

[0278] The single tlc spot is a mixture of four isomers which are separated after derivatization into the compounds of Examples 77 to 79 and 87 to 97 below.

[0279] Following the above procedure (Steps A-E), except using Compound (−)-52.0 (17 g), a mixture of 58.0a and 58.0b is obtained as a light solid that appears as a single tic spot (17 g). MS(ES) m/z 535 (MH⁺).

PREPARATIVE EXAMPLE 42

[0280]

[0281] To 2.5 kg of (R)-(−)-camphorsulfonic acid stirring at 60° C. in 1250 ml of distilled water was added a soution of the potassium salt of 2-carboxyl-piperazine (565 gm, 3.35 mol). The mixture was allowed to stir at 95° C. until completely dissolved. The solution was allowed to stand at ambient temperature for 48 hrs. The resulting precipitate was filtered to obtain 1444 gm of damp solid. The solids were then dissolved in 1200 ml of distilled water and heated on a steam bath until all solids dissolved. The hot solution was then set aside to cool slowly for 72 hrs. The crystalline solids were filtered to give 362 gm of the pure 2-R-enantiomeric product as a white crystalline-solid. [α]_(D)=−14.9°.

[0282] 2-R-carboxyl-piperazine-di-(R)-(−) -camphorsulfonic acid (Preparative Example 42) (362 gm, 0.608 mol) was dissolved in 1.4 L of distilled water and 1.4 L of methanol. 75 ml of 50% NaOH was dripped in to the stirred reaction mixture to obtain a ˜pH 9.5 solution. To this solution was added di-tert-butyl-dicarbonate (336 gm, 1.54 mol) as a solid. The pH dropped to ˜7.0. The pH of the reaction mixture was maintained at 9.5 with 50% NaOH (total of 175 ml), and the reaction mixture stirred for 2.5 hours to obtain a white precipitate. The reaction mixture was diluted to 9 L with ice/water followed by washing with 2 L of ether. The ether was discarded and the pH of the aqueous layer adjusted to pH 3.0 by the portionwise addition of solid citric acid. The acidified aqueous layer was then extracted with dichloro-methane 3× with 2 L. The organic layers were combined, dried over sodium sulfate, filtered and evaporated to obtain 201.6 gm of title compound as a white glassy solid. FABMS (M+1)=331.

[0283] To an ice cold solution N,N-dimethylformamide (49.6 ml,) was added, dropwise, thionylchloride (46.7 ml) over a period of 5 minutes in a 5 L round bottom flask under a nitrogen atmosphere. The reaction mixture was allowed to stir for 5 min. and the ice bath removed and the reaction mixture allowed to stir at ambient temperature for 30 min. The reaction mixture was cooled again in an ice bath and a solution of of N,N-di-tert-butoxycarbonyl-2-R-carboxyl-piperazine (Preparative Example 43) (201.6 gm, 0.61 mmol) in 51.7 ml of pyridine and 1.9 L of acetonitrile was cannulated into the reaction mixture. The reaction mixture was allowed to warm to ambient temperature to obtain a yellowish turbid solution. After stirring at ambient temperature for 18 hours, the reaction mixture was filtered and the filtrate poured into ice water (7 L) and then extracted with 4×2 L of ethyl acetate, dried over sodium sulfate, filtered and evaporated to dryness under vacuo to obtain 115.6 gm (73%) of the title product as a white solid.

[0284] 1N-p-Cyanobenzyl histamine (0.34, 1.5 mmol) (prepared as described in Preparative Example 163) was added to a solution of the Boc-anhydride (Preparative Example 44) (0.38 gm, 1.5 mmol) in 10 ml of dichloromethane and stirred under a nitrogen. After 1 hr, 0.15 gm more of the Boc-anhydride was added and the reaction monitored for completion by normal phase tlc using 10% methanol/dichloromethane as the eluent. After the reaction went to completion (˜1 hour), 0.25 ml (2 mmol) of cyclohexyl isocyanate was added to the reaction mixture and stirred for 1 hour. The reaction mixture was poured into brine and extracted with dichloromethane (3×). The dichloromethane layers were combined, dried over MgSO₄, filtered and evaporated to dryness. The residue was chromatographed on a flash column of silica gel using 5% methanol/dichloromethane to obtain 0.714 gm of pure title compound as a solid. FABMS (M+1)=564.

[0285] N-(2,3-Epoxypropyl)phthaiimide (2.3 gm, 11.3 mmol) was dissolved in N,N-dimethylformamide and imidazole (1.53 gm, 1.5 eq.) was added and the reaction mixture stirred at 90 ° C. for 5 hours. Brine was added and the product extracted with ethylacetate to obtain the title product (0.67 gm).

[0286] 1-Phthalamido-2-hydroxy-3-1-H-imidazole-propane (from Preparative Example 46) (0.6 gm) was dissolved in ethanol and 5 ml of hydrazine hydrate added. The reaction mixture was refluxed for 3 hours. The reaction mixture was cooled to ambient temperature and the resulting precipitate filtered. The filtrate was evaporated to dryness to obtain the title product which was used without further purification.

[0287] 1-Amino-2-hydroxy-3-1-H-imidazole-propane (from Preparative Example 47) (2.2 mmol) was added to a solution of the Boc-anhydride (Preparative Example 44) (0.57 gm, 2.2 mmol) in 10 ml of dichloromethane and stirred under nitrogen. After 1 hr, 0.15 gm more of the Boc-anhydride was added and the reaction monitored for completion by normal phase tlc using 10% methanol/dichloromethane as the eluent. After the reaction went to completion (1 hour), 0.85 ml (6.6 mmol) of cyclohexyl-isocyanate was added to the reaction mixture and stirred for 1 hour. The reaction mixture was poured into brine and extracted with dichloromethane (3×). The dichloromethane layers were combined, dried over MgSO₄, filtered and evaporated to dryness. The residue was chromatographed on a flash column of silica gel using 5% methanol/dichloromethane to obtain 0.487 gm of pure title compound as a solid.

[0288] 2-Carboxy-piperazine-dicamphorsulfonic acid salt (Preparative Example 42) (17.85 gm, 30 mmole) was dissolved in 180 ml of distilled water. Dioxane (180 mL) was added and the pH adjusted to 11.0 with 50% NaOH. The reaction mixture was cooled to 0-5° C. in an ice-MeOH bath and a solution of benzyl-chloroformate (4.28 mL, 30 mmol) in 80 mL of dioxane was added over a period of 30-45 minutes while stirring at 0-5° C. and keeping the pH at 10.5 to 11.0 with 50% NaOH. After the addition was complete, stirring was continued for 1 hr. The reaction mixture was then evaporated to dryness (to get rid of the dioxane for extraction). The residue was dissolved in 180 mL of dist. water and the pH adjusted slowly to 4.0 with 1N HCl. The aqueous solution was washed with 3×180 mL of ethyl acetate (The ethyl acetate was dried over MgSO₄, filtered, and evaporated to obtain N,N-di—CBZ-2-carboxy-piperazine and saved). The pH of the aqueous layer, which contains the desired product, was adjusted to 10.5 to 11.0 with 50% NaOH and solid di-tert-butyl-dicarbonate (7.86 gm, 36 mmol) was added and the mixture was stirred while keeping the pH at 10.5 to 11.0 with 50% NaOH. After 1 hr. the pH stabilized. When reaction was complete, the reaction mixture was washed with 2×180 mL of Et₂O. The aqueous layer was cooled in an ice bath and adjusted pH to 2.0 with 1N HCl (slowly). Extract the product with 3×200 mL of ethyl acetate. Dry over MgSO₄, filter and evaporate to obtain 9.68 gm (88%) of pure product as a white solid.

[0289] 4-N-CBZ-1N-Boc-2-carboxy-piperazine (Preparative Example 49) (9.6 gm, 26.3 mmol) was dissolved in 100 mL of absolute ethanol in a hydrogenation vessel. The vessel was flushed with nitrogen and 3 gm of 10% Pd/C (50% by weight with water) was added. The mixture was hydrogenated at 55 psi of H₂ for 18 hours. After 18 hrs, the reaction mixture had a precipitate. The tlc was checked (30% MeOH/NH₃/CH₂Cl₂). The reaction mixture was filtered on a pad of Celite, and the pad washed with EtOH followed by distilled water. The filtrate was evaporated to ˜⅓ the volume (to get rid of the EtOH) and 200 mL of distilled water was added. The aqueous layer was extracted with ethyl acetate three times (the ethyl acetate layer contained pure N,N-Di-Boc-2-carboxy-piperazine which was saved). The water layer was evporated to dryness and evaporated from methanol two times to obtain 3.98 (17.37 gm, mmol) of pure product.

[0290] The tricyclic alcohol (Preparative Example 40 in WO 95/10516)

[0291] (5.6 gm, 17.33 mmol) was dissolved in 56 ml of dichloromethane and 2.46 ml of thionyl chloride was added while stirring under a dry nitrogen atmosphere. After 5 hrs. the tlc was checked (by adding an aliquot of the reaction mixture to 1N NaOH and shaking with dichloromethane and checking the dichloromethane layer by tlc using 50% EtOAc/Hexanes as the eluent). The mixture was evaporated to give a gum which was evaporated from dry toluene twice and once from dichloro-methane to give the 11-chloro derivative as a foamy solid which was used without further purification. The resulting 11-chloro-tricyclic compound was dissolved in 100 ml of dry DMF, 1N-Boc-2-carboxy-piperazine (Preparative Example 50) (3.98 gm) was added followed by 12.11 ml of triethylamine and the mixture stirred at ambient temperature under a nitrogen atmosphere. After 24 hours the DMF was evaporated and the residue dissolved in 200 ml of ethyl acetate and washed with brine. The brine layer was washed with ethyl acetate two more times and the ethyl acetate layers combined, dried over magnesium sulfate, filtered, and evaporated to give a foamy solid. The solid was chromatographed on a 1½″×14″ column of silica gel eluting with 2 L of 0.4% 7N MeOH/NH₃:CH₂Cl₂, 6 L of 0.5% 7N MeOH/—NH₃:CH₂Cl₂, 2 L of 0.65% 7N MeOH/NH₃:CH₂Cl₂, 2 L of 0.8% 7N MeOH/NH₃:CH₂Cl₂, 4 L of 1% 7N MeOH/NH₃:CH₂Cl₂, 2 L of 3% 2N MeOH/NH₃:CH₂Cl₂, 2 L of 5% 2N MeOH/NH₃:CH₂Cl₂, 2 L of 10% 2N MeOH/NH₃:CH₂Cl₂, 2 L of 15% 2N MeOH/NH₃:CH₂Cl₂, 4 L of 20% 2N MeOH/NH₃:CH₂Cl₂ to obtain 4.63 gm of final product.

[0292] The title compound from Preparative Example 51 (1 gm, 1.86 mmol) was dissolved in 50 ml of DMF and 1-amino-3-propanol (0.214 ml, 1.5 eq.), DEC (0.71 gm, 2 eq.), HOBT (0.5 gm, 2 eq.), and N-methyl-morpholine (1.02 ml, 5 eq.) was added and the reaction mixture stirred for 18 hours. The reaction mixture was added to brine and the product extracted with ethyl acetate 3 times to obtain a crude oil, after the solvent was evaporated under reduced pressure, which was purified by chromatography on a silica gel column 20%-50% ethyl acetate/hexanes as the eluent. The product containing fractions were pooled to obtain 0.67 gm (60%) of pure title compound.

[0293] 2-Anminoimidazole (8 g, 60 mmol) was dissolved in 200 ml of DMF and cooled in an ice bath. Sodium hydride 60% oil dispersion (2.4 g, 60 mmol) was added portionwise and the reaction mixture stirred for 1 hour. N-(3-Bromopropyl)-phthaiimide (16 g, 74 mmol) was added and the reaction mixture stirred for ½ hour at 0° C., 1 hour at ambient temperature, and then 1 hour at 85° C. The reaction mixture was then cooled to ambient temperature and added to brine and extracted with ethyl acetate to obtain the crude product which was purified by column chromatography using 2% methanol/methylene chloride to obtain 4.88 gm of title compound.

[0294] 0.5 gm of 1-phthalimidopropyl-2-aminoimidazole (from Preparative Example 53) was refluxed in 20 ml of 6N HCl for 6 hours. The mixture was washed with ethyl acetate and the aqueous layer evaporated to dryness to obtain 0.45 g of the title product.

[0295] 1-Aminopropyl-2-aminoimidazole (Preparative Example 54) (0.25 gm) and N,N-di-butoxycarbonyl-2-R-carboxyl-piperazine (from Preparative Example 43) (0.32 gm) was dissolved in 10 ml of DMF. DEC (0.2 gm.), 1-hydroxybenzotriazole (0.135 gm), and N-methyl-morpholine (0.54 ml) was added and the reaction mixture stirred for 5 hours. The reaction was poured into brine and extracted with dichloromethane to obtain 0.43 gm of the title product after chromatography on silica gel using 2% methanol/-dichloromethane up to 10%. FABMS M+1=453.3.

[0296] 1-Aminopropyl-2-aminoimidazolyl-N1,N4-di-tert.butyl-1,2(R)-piperazinedicarboxamide (Preparative Example 55) (0.38 gm) was dissolved in 20 mL of dichloromethane and 0.24 ml of triethylamine. Benzyloxycarbonyl-N-hydroxysuccinimide (0.22 gm) was added and the reaction mixture stirred for 18 hours at ambient temperature. The reaction mixture was washed with brine and chromatographed on a silica gel column using ethyl acetate as the eluent to obtain 0.39 gm of title product. FABMS M+1=587.3.

[0297] 1-benzyloxycarbonylaminopropyl-2-aminoimidazolyl-N1,N4-di-tert.butyl-1,2(R)-piperazinedicarboxamide (Preparative Example 56) (0.4 gm) was dissolved in 3 ml of dichloromethane and 1 ml of trifluoroacetic acid was added and the reaction mixture stirred for 3 hours at ambient temperature. The reaction mixture was then evaporated to dryness to obtain the pure title product.

[0298] 1-benzyloxycarbonylaminopropyl-2-aminoimidazolyl-1,2(R)-piperazinedicarboxamide (Preparative Example 57) was dissolved in 50 ml of DMF and 0.46 ml of triethylamine. 3-Bromo-8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (171 mg) was added and the reaction mixture stirred for 24 hours. The reaction mixture was added to brine and extracted with dichloromethane to obtain 82 mg of pure title product after silica gel chromatography using methanol/dichloro-methane as the eluent. FABMS (M+1)=694.

[0299] 1-tert-Butoxycarbonylaminopropyl-imidazole (0.991 gm, 4.4 mmol) was dissolved in 25 mol of dry THF and cooled to −78° C. A 2.5M solution of n-butyllithium (3.88 ml, 9.68 mmol) in cyclohexanes was added dropwise and the reaaction stirred for ½ hour. Acetaldehyde (0.49 ml, 8.8 mmol) was added and the reaction stirred for ½ hour. The reaction mixture was allowed to warm to ambient temperature. The reaction was diluted with ethyl acetate and washed with brine. The ethyl acetate layer was evaporated to obtain a gum which was chromatographed on silica gel to obtain 0.54 gm of title product. (MH⁺=170).

[0300] 1-tert-Butoxycarbonylaminopropyl-2-hydroxyethyl-imidazole (Preparative Example 59) (0.5 1 gm) was dissolved in trifluoroacetic acid and stirred for 3-4 hours. The mixture was evaporated to dryness to obtain the pure TFA salt of the title compound.

[0301] 1-N-Trityl-4-iodoimidazole (1.91 gm) was dissolved in 20 ml of dichloromethane and 1.46 ml of ethyl magnesiumbromide was added while stirring. After 15 min. N-Boc-phenylalanine aldehyde (0.5 gm) was added and the reaction mixture was stirred for 18 hours. The reaction mixture was washed with saturated ammonium chloride, dried over magnesium sulfate, and chromatographed on silica gel to obtain 0.8 gm of the intermediate blocked product. FABMS (M+1)=561. This was then treated with 4M HCl/dioxane for 18 hours. The mixture was evaporated to dryness and dissolved in distilled water and washed with ethyl acetate. The aqueous layer was evaporated to obtain pure title product. (MH⁺=218).

[0302] A mixture of N-(3-bromopropyl)phthalimide (12.3 g, 46 mmol), 4-methylimidazole (3.78 g, 46 mmol), sodium hydride (60% in mineral oil, 1.84 g, 46 mmol) and anhydrous DMF (50 mL) was stirred at 25-70° C. under N₂ overnight. The mixture was concentrated in vacuo to give a residue which was diluted with dichloromethane, filtered, concentrated in vacuo and purified by flash column chromatography (silica gel) using 1% MeOH—CH₂Cl₂ saturated with aqueous ammonium hydroxide to give the title compound as an oil (8.04 g, 65%, MH⁺=270).

[0303] To a solution of the title compound from Step A (8.02 g, 29.8 mmol) dissolved in absolute EtOH (150 mL) was added hydrazine-mono hydrate (15 mL) and the mixture was stirred at reflux for 12 h under N₂. The mixture was diluted with dichloromethane, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel) using 5% MeOH—CH₂Cl₂ saturated with aqueous ammonium hydroxide to give the title compound as an oil (2.95 g, 71%, MH⁺=140).

PREPARATIVE EXAMPLES 63-67

[0304] Following the procedure set forth in Preparative Example 62, but using the substituted imidazole in Table 3 below instead of 4-methylimidazole in Step A, the amines (Product) listed in Table 3 were prepared. TABLE 3 Prep. Yield Ex. Imidazole Product MH⁺ (%) 63

154 70

64

154 60

65

154 68 66

140 46 66.1

— 88

PREPARATIVE EXAMPLE 67

[0305] If the procedure set forth in Preparative Example 62 were followed, except the imidazole

[0306] would be used instead of 4-methylimidazole in Step A, the amine

[0307] would be obtained.

PREPARATIVE EXAMPLE 67.1

[0308] If the procedure set forth in Preparative Example 62 were followed, except the imidazole

[0309] would be used instead of 4-methylimidazole in Step A, the amine

[0310] would be obtained.

[0311] A mixture of 2-chloroethylamine hydrochloride (7.66 g, 66 mmol), 2,4-dimethylimidazole (5.88 g, 61 mmol), tetrabutyl ammonium sulfate (0.83 g, 2.5 mmol), solid NaOH (8.81 g, 220 mmol) and anhydrous acetonitrile (80 mL) was stirred at reflux for 48 h under N₂. The mixture was filtered, concentrated in vacuo and purified by flash column chromatography (silica gel) using 2% MeOH—CH₂Cl₂ saturated with aqueous ammonium hydroxide to give the title compound as an oil (10.7 g, 100%, MH⁺=140).

PREPARATIVE EXAMPLES 69-73

[0312] Following the procedure set forth in Preparative Example 68, but using the substituted imidazole or triazole in Table 4 below instead of 2,4-dimethylimidazole, the amines (Product) listed in Table 4 were prepared. TABLE 4 Prep. Yield Ex. Imidazole Product MH⁺ (%) 69

126 75

70

112 65 71

176 55 72

126 53 73

(A): 163 (A): 60

(B): 163 (B): 40

[0313]

[0314] A mixture of 1-(3-aminopropyl)imidazole (37.1 g, 297 mmol), benzaldehyde (30 g, 283 mmol), 3 Å molecular sieves (50 g), sodium acetate (24.1 g, 283 mmol) and anhydrous methanol (700 mL) was stirred at room temperature under N₂ overnight. The mixture was 

What is claimed is:
 1. A compound of the formula:

or a pharmaceutically acceptable salt or solvate thererof, wherein: one of a, b, c and d represents N or N⁺O⁻, and the remaining a, b, c and d groups represent CR¹ or CR²; or each of a, b, c, and d are independently selected from CR¹ or CR²; X represents N or CH when the optional bond (represented by the dotted line) is absent, and represents C when the optional bond is present; the dotted line between carbon atoms 5 and 6 represents an optional bond, such that when a double bond is present, A and B independently represent —R¹⁵, halo, —OR¹⁶, —OCO₂R¹⁶ or —OC(O)R¹⁵, and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H₂, —(OR¹⁶)₂, H and halo, dihalo, alkyl and H, (alkyl)₂, —H and —OC(O)R¹⁵, H and —OR¹⁵, ═O, aryl and H, ═NOR¹⁵ or —O—(CH₂)_(p)—O—wherein p is 2, 3 or 4; each R¹ and each R² is independently selected from H, halo, —CF₃, —OR¹⁵, —COR¹⁵, —SR¹⁵, —S(O)_(t)R¹⁶ (wherein t is 0, 1 or 2, —N(R¹⁵)₂, —NO₂, —OC(O)R¹⁵, —CO₂R¹⁵, —OCO₂R¹⁶, —CN, —NR¹⁵COOR¹⁶, —SR¹⁶C(O)OR¹⁶, —SR¹⁶N(R¹⁷)₂ (provided that R¹⁶ in —SR¹⁶N(R¹⁷)₂ is not —CH₂—) wherein each R¹⁷ is independently selected from H or —C(O)OR¹⁶, benzotriazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazol-5-ylthio, alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo, —OR¹⁵ or —CO₂R¹⁵; R³ and R⁴ are the same or different and each independently represents H, any of the substituents of R¹ and R², or R³ and R⁴ taken together represent a saturated or unsaturated C₅-C₇ fused ring to the benzene ring (Ring III); R⁵, R⁶, and R⁷ each independently represents H, —CF₃, —COR¹⁵, alkyl or aryl, said alkyl or aryl optionally being substituted with —OR¹⁵, —SR¹⁵, —S(O)_(t)R¹⁶, —NR¹⁵COOR¹⁶, —N(R¹⁵)₂, —NO₂, —COR¹⁵, —OCOR¹⁵, —OCO₂R¹⁶, —CO₂R¹⁵, OPO₃R¹⁵, or R⁵ is combined with R⁶ to represent ═O or ═S; R⁸ is selected from: H, C₃ to C₄ alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, substituted alkyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl; the substutuents for the R⁸ substituted groups being selected from: alkyl, aryl, arylalkyl, cycloalkyl, —N(R¹⁸)₂, —OR¹⁸, cycloalkyalkyl, halo, CN, —C(O)N(R¹⁸)₂, —SO₂N(R¹⁸)₂ or —CO₂R¹⁸; provided that the —OR¹⁸ and —N(R¹⁸)₂ substituents are not bound to the carbon that is bound to the N of the —C(O)NR⁸-moiety; each R¹⁸ is independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl; R⁹ and R¹⁰ are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or —CON(R¹⁸)₂ (wherein R¹⁸ is as defined above); and the substitutable R⁹ and R¹⁰ groups are optionally substituted with one or more substituents selected from: alkyl, cycloalkyl, arylalkyl, or heterarylalkyl; or R⁹ and R¹⁰ together with the carbon atom to which they are bound, form a C₃ to C₆ cycloalkyl ring; R¹¹ and R¹² are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, —CON(R¹⁸)2 —OR¹⁸ or —N(R¹⁸)₂; wherein R¹⁸ is as defined above; provided that the —OR¹⁸ and —N(R¹⁸)₂ groups are not bound to a carbon atom that is adjacent to a nitrogen atom; and wherein said substitutable R¹¹ and R¹² groups are optionally substituted with one or more substituents selected from: alkyl, cycloalkyl, arylalkyl, or heterarylalkyl; or R¹¹ and R¹² together with the carbon atom to which they are bound, form a C₃ to C₆ cycloalkyl ring; R¹³ is an imidazolyl ring selected from:

 wherein R¹⁹ is selected from: (1) H, (2) alkyl, (3) alkyl, (4) aryl, (5) arylalkyl, (6) substituted arylalkyl wherein the substituents are selected from halo or CN, (7) —C(aryl)₃ or (8) cycloalkyl; said imidazolyl ring 2.0 optionally being substituted with one or two substituents, and said imidazole ring 4.0 optionally being substituted with 1-3 substituents, and said imidazole ring 4.1 being optionally substituted with one substituent wherein said optional substituents for rings 2.0, 4.0 and 4.1 are independently selected from: —NHC(O)R¹⁸, —C(R³⁴)₂OR³⁵, —OR¹⁸, —SR¹⁸, F, Cl, Br, alkyl, aryl, arylalkyl, cycloalkyl, or —N(R¹⁸)₂ (wherein each R¹⁸ is independently selected); wherein R¹⁸ is as defined above; wherein each R³⁴ is independently selected from H or ally; wherein R³⁵ is selected from H, —C(O)OR²⁰, or —C(O)NHR²⁰, and R²⁰ is as defined below; Q represents an aryl ring, a cycloalkyl ring or a heteroaryl ring, said Q is optionally substituted with 1 to 4 substituents inedependently selected from halo, ally, aryl, —OR¹⁸, —N(R¹⁸)₂ (wherein each R¹⁸ is independently selected), —OC(O)R¹⁸, or —C(O)N(R¹⁸)₂ (wherein each R¹⁸ is independently selected), and wherein R¹⁸ is as defined above; R¹⁴ is selected from:

R¹⁵ is selected from: H, alkyl, aryl or arylalkyl; R¹⁶ is selected from: alkyl or aryl; R²⁰ is selected from: H, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl, provided that R²⁰ is not H when R¹⁴ is group 5.0 or 8.0; when R²⁰ is other than H, then said R²⁰ group is optionally substituted with one or more substituents selected from: halo, alkyl, aryl, —OC(O)R¹⁸, —OR¹⁸ or —N(R¹⁸)₂, wherein each R¹⁸ group is the same or different, and wherein R¹⁸ is as defined above, provided that said optional substituent is not bound to a carbon atom that is adjacent to an oxygen or nitrogen atom; R²¹ is selected from: H, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl; when R²¹ is other than H, then said R²¹ group is optionally substituted with one or more substituents selected from: halo, alkyl, aryl, —OR¹⁸ or —N(R¹⁸)₂, wherein each R¹⁸ group is the same or different, and wherein R¹⁸ is as defined above, provided that said optional substituent is not bound to a carbon atom that is adjacent to an oxygen or nitrogen atom; n is 0-5; each R³² and R³³ for each n are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, —CON(R¹⁸)₂ —OR¹⁸ or ═—N(R¹⁸)₂; wherein R¹⁸ is as defined above; and wherein said substitutable R³² and R³³ groups are optionally substituted with one or more substituents selected from: alkyl, cycloalkyl, arylalkyl, or heterarylalkyl; or R³² and R³³ together with the carbon atom to which they are bound, form a C₃ to C₆ cycloalkyl ring; and R³⁶ is selected from branched alkyl, unbranched alkyl, cycloalkyl, heterocycloalkyl, or aryl; and provided that: (1) when R¹⁴ is selected from: group 6.0, 7.0, 7.1 or 8.0, and X is N, then R⁸ is selected from: C₃ to C₁₀alkyl, substituted C₃ to C₁₀ alkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl; and (2) when R¹⁴ is selected from: group 6.0, 7.0, 7.1 or 8.0, and X is N, and R⁸ is H, then the alkyl chain between R¹³ and the amide moiety is substituted.
 2. The compound of claim 1 having the structure:


3. The compound of claim 1 having the structure:


4. The compound of claim 1 wherein R¹ to R⁴ is independently selected from H, Br or Cl; R⁵ to R⁷ is H; a is N and the remaining b, c and d substituents are carbon; A and B are H₂; n is 0 or 1; and R¹³ is group 2.0 or 4.0.
 5. The compound of claim 1 wherein R¹ to R⁴ is independently selected from H, Br or Cl; R⁵ to R⁷ is H; a,b, c and d are carbon; A and B are H₂; n is 0 or 1; and R¹³ is group 2.0 or 4.0.
 6. The compound of claim 1 wherein R⁸ is selected from: arylalkyl, substituted arylalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, heteroarylalkyl or substituted heteroarylalkyl.
 7. The compound of claim 1 wherein R⁸ is selected from arylalkyl, cycloalkylalkyl, or heteroarylalkyl.
 8. The compound of claim 1 wherein: (a) R⁹ and R¹⁰ are independently selected from: H, alkyl, —C(O)N(R¹⁸)₂, or arylalkyl; (b) R¹¹ and R¹² are independently selected from: H, alkyl, substituted aryl, —OR¹⁸, or R¹¹ and R¹² taken together with the carbon atom to which they are bound form a cycloalkyl ring; (c) R³² and R³³ are independently selected from: H, —OR¹⁸, arylalkyl or aryl; (d) R¹⁹ is selected from: —C(O)N(R¹⁸)₂, alkyl, arylalkyl, or —C(aryl),; and (e) said optional R¹³ substitutents are selected from: —N(R¹⁸)₂, —NHC(O)R¹⁸, —C(R³⁴)₂OR³⁵, alkyl, or cycloalkyl substituted with —OH provided that the —OH substitutent is not bound to a carbon that is adjacent to an oxygen atom.
 9. The compound of claim 1 wherein R¹⁴ is group 5.0 and R²⁰ is selected from: alkyl, arylalkyl, heterocycloalkyl, aryl, aryl substituted with halo, cycloalkyl, or cycloalkyl substituted with alkyl.
 10. The compound of claim 1 wherein R¹⁴ is: (a) 6.0 wherein R²⁰ and R²¹ are independently selected from: H, cycloalkyl, alkyl, aryl, or arylalkyl; (b) 7.0 wherein R²⁰ is selected from: heteroaryl, cycloalkyl, heterocycloalkyl, alkoxy, heterocycloalkyl substituted with —C(O)N(R¹⁸)₂; (c) 7.1 wherein R³⁶ is selected from: cycloalkyl or heterocycloalkyl; or (d) 8.0 wherein R²⁰ is selected from: alkyl or cycloalkyl.
 11. The compound of claim 1 wherein: (a) R¹ to R⁴ is independently selected from H, Br or Cl; (b) R⁵to R⁷ is H; (c) a is N and the remaining b, c and d substituents are carbon; (d) A and B are H₂; (e) n is 0 or 1; (f) R¹³ is group 2.0 or 4.0; (g) R⁸ is selected from: arylalkyl, substituted arylalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, heteroarylalkyl, or substituted heteroarylalkyl; (h) X is CH or N; (i) R²⁰ for 5.0 is selected from: (1) alkyl, (2) arylalkyl, (3) heterocycloalkyl, (4) aryl, (5) aryl substituted with halo, (6) cycloalkyl, (7) cycloalkyl substituted with alkyl, or (8) cycloalkyl substituted with —OC(O)R¹⁸ or —OH provided said —OH substitutent is not bound to a carbon atom that is adjacent to an oxygen atom; (j) R²⁰ and R²¹ for 6.0 are independently selected from: H, cycloalkyl, alkyl, aryl, or arylalkyl; (k) R²⁰ for 7.0 is selected from: heteroaryl, cycloalkyl, alkoxy, heterocycloalkyl substituted with —C(O)N(R¹⁸)₂; (l) R³⁶ for 7.1 is selected from heterocycloalkyl or cycloalkyl; and (m) R²⁰ for 8.0 is selected from: alkyl or cycloalkyl.
 12. The compound of claim 11 wherein: (a) R⁹ and R¹⁰ are independently selected from: H, alkyl, —C(O)N(R¹⁸)₂, or arylalkyl; (b) R¹¹ and R¹² are independently selected from: H, alkyl, substituted aryl, —OR¹⁸, or R¹¹ and R¹² taken together with the carbon atom to which they are bound form a cycloalkyl ring; (c) R³² and R³³ are independently selected from: H, —OR¹⁸, arylalkyl or aryl; (d) R¹⁹ is selected from: —C(O)N(R¹⁸)₂, alkyl, arylalkyl, or —C(aryl)₃; and (e) said optional R¹³ substitutents are selected from: —N(R¹⁸)₂, —NHC(O)R¹⁸, —C(R³⁴)₂OR³⁵, or alkyl.
 13. The compound of claim 12 wherein: (a) R⁸ is selected from arylalkyl, cycloalkylalkyl, or heteroarylalkyl; (b) R⁹ and R¹⁰ are independently selected from: H or benzyl; (c) R¹¹ and R¹² are independently selected from: H, —CH₃, —CH₂CH(CH₃)₂, —(CH₂)₃CH₃, benzyl, ethyl, p-chlorophenyl, —OH, or R¹¹ and R¹² taken together with the carbon atom to which they are bound form a cyclopropyl ring; (d) R³² and R³³ are independently selected from: H, phenyl, —OH or benzyl; (e) R¹⁹ is selected from: —C(O)NH-cyclohexyl, —C(phenyl)₃, H, methyl or ethyl; (f) said optional R¹³ substitutents are selected from: —CH₃, —CH₂OH, —CH₂OC(O)O-cyclohexyl, —CH₂OC(O)O-cyclopentyl, ethyl, isopropyl, NH2, or —NHC(O)CF₃; (g) R²⁰ for group 5.0 is selected from: t-butyl, ethyl, benzyl, —CH(CH₃)₂, —CH₂CH(CH₃)₂, —(CH₂)₂CH₃, n-butyl, n-hexyl, n-octyl, p-chlorophenyl, cyclohexyl, cyclopentyl,

(h) R²⁰ and R²¹ for 6.0 are independently selected from: cyclohexyl, t-butyl, H, —CH(CH₃)₂, ethyl, —(CH₂)₂CH₃, phenyl, benzyl, —(CH₂)₂phenyl, or —CH₃; (i) R²⁰ for 7.0 is selected from: 4-pyridylNO, —OCH₃, —CH(CH₃)₂, -t-butyl, H, propyl, cyclohexyl or

(j) R³⁶ for 7.1 is selected from: cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl,

and (k) R²⁰ for 8.0 is selected from: methyl, i-propyl or cyclohexylmethyl.
 14. The compound of claim 13 wherein R³ is selected from: benzyl, —CH₂C(CH₃)₂, —CH₂-cyclohexyl, —CH₂-cyclopropyl, —(CH₂)₂CH₃,


15. The compound of claim 14 wherein: (a) R⁸ is selected from: benzyl or —CH₂-cyclopropyl; (b) R²⁰ for 5.0 is cyclohexyl; (c) R²⁰ for 6.0 is selected from: t-butyl, i-propyl, or cyclohexyl; and R²¹ is selected from: H, —CH₃ or i-propyl; (d) R²⁰ for 7.0 is selected from: cyclohexyl, cyclopentyl, or i-propyl; (e) R³⁶ for 7.1 is selected from: cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; and (d) R²⁰ for 8.0 is methyl.
 16. The compound of claim 15 wherein said compound is the 2R isomer.
 17. The compound of claim 1 wherein R⁸ is H and the alkyl chain between the amide substituent —C(O)NR⁸ and R¹³ is substituted.
 18. The compound of claim 1 wherein when R¹⁴ is group 5.0, and X is N, and R⁸ is H, then (a) the alkyl chain between R¹³ and the amide moiety is substituted and/or (b) R⁹ and R¹⁰, and/or R¹¹ and R¹², are taken together to form a cyloalkyl ring.
 19. A compound of the formula:

or a pharmaceutically acceptable salt or solvate thererof, wherein: one of a, b, c and d represents N or N⁺O⁻, and the remaining a, b, c and d groups represent CR¹ or CR²; or each of a, b, c, and d are independently selected from CR¹ or CR²; X represents N or CH when the optional bond (represented by the dotted line) is absent, and represents C when the optional bond is present; the dotted line between carbon atoms 5 and 6 represents an optional bond, such that when a double bond is present, A and B independently represent —R¹⁵, halo, —OR¹⁶, —OCO₂R¹⁶ or —OC(O)R¹⁵, and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H₂, —(OR¹⁶)₂, H and halo, dihalo, alkyl and H, (alkyl)₂, —H and —OC(O)R¹⁵, H and —OR¹⁵, ═O, aryl and H, ═NOR¹⁵ or —O—(CH₂)_(p)—O—wherein p is 2, 3 or 4; each R¹ and each R² is independently selected from H, halo, —CF₃, —OR¹⁵, —COR¹⁵, —SR¹⁵, —S(O)_(t)R¹⁶ (wherein t is 0, 1 or 2, —N(R¹⁵)₂, —NO₂, —OC(O)R¹⁵, —CO₂R¹⁵, —OCO₂R¹⁶, —CN, —NR¹⁵COOR¹⁶, —SR¹⁶C(O)OR¹⁶, —SR¹⁶N(R¹⁷)₂ (provided that R¹⁶ in —SR¹⁶N(R¹⁷)₂ is not —CH₂—) wherein each R¹⁷ is independently selected from H or —C(O)OR¹⁶, benzotriazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazol-5-ylthio, alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo, —OR¹⁵ or —CO₂R¹⁵; R³ and R⁴ are the same or different and each independently represents H, any of the substituents of R¹ and R², or R³ and R⁴ taken together represent a saturated or unsaturated C₅-C₇ fused ring to the benzene ring (Ring III); R⁵, R⁶, and R⁷ each independently represents H, —CF₃, —COR¹⁵, alkyl or aryl, said alkyl or aryl optionally being substituted with —OR¹⁵, —SR¹⁵, —S(O)_(t)R¹⁶, —NR¹⁵COOR¹⁶, —N(R¹⁵)₂, —NO₂, —COR¹⁵, —OCOR¹⁵, —OCO₂R¹⁶, —CO₂R¹⁵, OPO₃R¹⁵, or R⁵ is combined with R⁶ to represent ═O or ═S; R⁸ is selected from: H, C₃ to C₄ alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, substituted alkyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl; the substutuents for the R⁸ substituted groups being selected from: alkyl, aryl, arylalkyl, cycloalkyl, —N(R¹⁸)₂, —OR¹⁸, cycloalkyalkyl, halo, CN, —C(O)N(R¹⁸)₂, —SO₂N(R¹⁸)₂ or —CO₂R¹⁸; provided that the —OR¹⁸ and —N(R¹⁸)₂ substituents are not bound to the carbon that is bound to the N of the —C(O)NR⁸-moiety; each R¹³ is independently selected from: H, alkyl aryl, arylalkyl, heteroaryl or cycloalkyl; R⁹ and R¹⁰ are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or —CON(R¹⁸)₂ (wherein R¹⁸ is as defined above); and wherein said substitutable R⁹ and R¹⁰ groups are optionally substituted with one or more substituents selected from: alkyl, cycloalkyl, arylalkyl, or heterarylalkyl; or R⁹ and R¹⁰ together with the carbon atom to which they are bound, form a C₃ to C₆ cycloalkyl ring; R¹¹ and R¹² are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, —CON(R¹⁸)₂—OR¹⁸ or —N(R¹⁸)₂; wherein R¹⁸ is as defined above; provided that the —OR¹⁸ and —N(R¹⁸)₂ groups are not bound to a carbon atom that is adjacent to a nitrogen atom; and wherein said substitutable R¹¹ and R¹² groups are optionally substituted with one or more substituents selected from: alkyl, cycloalkyl, arylalkyl, or heterarylalkyl; or R¹¹ and R¹² together with the carbon atom to which they are bound, form a C₃ to C₆ cycloalkyl ring; R¹³ is an imidazolyl ring selected from:

 wherein R¹⁹ is selected from: (1) H, (2) alkyl, (3) alkyl, (4) aryl, (5) arylalkyl, (6) substituted arylalkyl wherein the substituents are selected from halo or CN, (7) —C(aryl)₃ or (8) cycloalkyl; said imidazolyl ring 2.0 optionally being substituted with one or two substituents and said imidazole ring 4.0 optionally being substituted with 1-3 substituents and said imidazole ring 4.1 being optionally substituted with one substituent wherein said optional substituents for rings 2.0, 4.0 and 4.1 are independently selected from selected from: —NHC(O)R¹⁸, —C(R³⁴)₂OR³⁵, —OR¹⁸, —SR¹⁸, F, Cl, Br, alkyl, aryl, arylalkyl, cycloalkyl, or —N(R¹⁸)₂; wherein R¹⁸ is as defined above; wherein each R³⁴ is independently selected from H or alkyl; wherein R³⁵ is selected from H, —C(O)OR²⁰, or —C(O)NHR²⁰, and R²⁰ is as defined below; Q represents an aryl ring, a cycloalkyl ring or a heteroaryl ring, said Q is optionally substituted with 1 to 4 substituents independently selected from halo, alkyl, aryl, —OR¹⁸, —N(R¹⁸)₂ (wherein each R¹⁸ is independently selected), —OC(O)R¹⁸, or —C(O)N(R¹⁸)₂ (wherein each R¹⁸ is independently selected), and wherein R¹⁸ is as defined above; R¹⁵ is selected from: H, alkyl, aryl or arylalkyl; R¹⁶ is selected from: alkyl or aryl; R²⁰ is selected from: alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl; said R²⁰ group is optionally substituted with one or more substituents selected from: halo, alkyl, aryl, —OC(O)R¹⁸, —OR¹⁸ or —N(R¹⁸)2, wherein each R¹⁸ group is the same or different, and wherein R¹⁸ is as defined above, provided that said optional substituent is not bound to a carbon atom that is adjacent to an oxygen or nitrogen atom; n is 0-5; each R³² and R³³ for each n are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, —CON(R¹⁸)₂ —OR¹⁸ or ═—N(R¹⁸)₂; wherein R¹⁸ is as defined above; and wherein said substitutable R³² and R³³ groups are optionally substituted with one or more substituents selected from: alkyl, cycloalkyl, arylalkyl, or heterarylalkyl; or R³² and R³³ together with the carbon atom to which they are bound, form a C₃ to C₆ cycloalkyl ring; and provided that when X is N, and R⁸ is H, then the alkyl chain between R¹³ and the amide moiety is substituted.
 20. The compound of claim 19 having the structure:


21. The compound of claim 19 having the structure:


22. The compound of claim 20 wherein: (a) R¹ to R⁴ is independently selected from H, Br or Cl; (b) R⁵ to R⁷ is H; (c) a, b, c, and d are carbon; (d) A and B are H₂; (e) n is 0 or 1; (f) R¹³ is group 2.0 or 4.0; (g) R⁸ is selected from: arylalkyl, substituted arylalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, heteroarylalkyl or substituted heteroarylalkyl; and (h) X is CH or N.
 23. The compound of claim 20 wherein: (a) R¹ to R⁴ is independently selected from H, Br or Cl; (b) R⁵ to R⁷ is H; (c) a is N and the remaining b, c and d substituents are carbon; (d) A and B are H₂; (e) n is 0 or 1; (f) R¹³ is group 2.0 or 4.0; (g) R⁸ is selected from: arylalkyl, substituted arylalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, heteroarylalkyl or substituted heteroarylalkyl; (h) X is CH or N; and (i) R²⁰ is selected from: alkyl, arylalkyl, heterocycloalkyl, aryl, aryl substituted with halo, cycloalkyl, cycloalkyl substituted with alkyl, or cycloalkyl substituted with —OH provided that said —OH substituent is not bound to a carbon adjacent to an oxygen atom.
 24. The compound of claim 23 wherein: (a) R⁹ and R¹⁰ are independently selected from: H, alkyl, —C(O)N(R¹⁸)₂, or arylalkyl; (b) R¹¹ and R¹² are independently selected from: H, alkyl, substituted aryl, —OR¹⁸, or R¹¹ and R¹² taken together with the carbon atom to which they are bound form a cycloalkyl ring; (c) R³² and R³³ are independently selected from: H, —OR¹⁸, arylalkyl or aryl; (d) R¹⁹ is selected from: —C(O)N(R¹⁸)₂, alkyl, arylalkyl, or —C(aryl)₃; and (e) said optional R¹³ substitutents are selected from: —N(R¹⁸)₂, —NHC(O)R¹⁸, —C(R³⁴)₂OR³⁵, or alkyl.
 25. The compound of claim 24 wherein: (a) R⁸ is selected from arylalkyl, cycloalkylalkyl, or heteroarylalkyl; (b) R⁹ and R¹⁰ are independently selected from: H or benzyl; (c) R¹¹ and R¹² are independently selected from: H, —CH₃, —CH₂CH(CH₃)₂, —(CH₂)₃CH₃, benzyl, ethyl, p-chlorophenyl, —OH, or R¹¹ and R¹² taken together with the carbon atom to which they are bound form a cyclopropyl ring; (d) R³² and R³³ are independently selected from: H, phenyl, —OH or benzyl; (e) R¹⁹ is selected from: —C(O)NH-cyclohexyl, —C(phenyl)₃, H, methyl or ethyl; (f) said optional R¹³ substitutents are selected from: —CH₃, —CH₂OH, —CH₂OC(O)O-cyclohexyl, —CH₂OC (O)O-cyclopentyl, ethyl, isopropyl, NH₂, or —NHC(O)CF₃; and (g) R²⁰ is selected from: t-butyl, ethyl, benzyl, —CH(CH₃)₂, —CH₂CH(CH₃)₂, —(CH₂)₂CH₃, n-butyl, n-hexyl, n-octyl, p-chlorophenyl, cyclohexyl, cyclopentyl,


26. The compound of claim 25 wherein R⁸ is selected from: benzyl, —CH₂C(CH₃)₂, —CH₂-cyclohexyl, —CH₂-cyclopropyl, —(CH₂)₂CH₃,


27. The compound of claim 26 wherein: (a) R⁸ is selected from: benzyl or —CH₂-cyclopropyl; and (b) R²⁰ is cyclohexyl.
 28. The compound of claim 27 which is a 3-Br-8-Cl-compound; an 8-Cl-compound; or a 10-Cl-compound.
 29. The compound of claim 25 wherein R⁹, R¹⁰, R¹¹, R¹², R³², and R³³ are H.
 30. The compound of claim 28 wherein R⁹, R¹⁰, R¹¹, R¹², R³², and R³³ are H.
 31. The compound of claim 20 wherein R⁸ is H and the alkyl chain between the amide substituent —C(O)NR⁸ and R¹³ is substituted.
 32. The compound of claim 1 selected from:


33. The compound of claim 1 selected from:


34. A compound of the formula:


35. A compound of the formula:


36. The compound of claim 1 selected from a compound of Example 1-22, 25, 45-66, 77, 78 Step B, 79, 80, 82-85, 86, 86A, 87-97, 99, 100, 102, 112-208, 208A, 209, 209A, 210, 210A, 210B, 211-220, 220A, 221-232, 234B, 234C, 234E, 235-254, 286A, 286B, 304-308, 326, 327, 328 or
 330. 37. The compound of claim 1 selected from a compound of Example 245, 246, 247, 248, 249, 250, 251, 252, 253 or
 254. 38. A compound selected from a compound of Example 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 81, 98, 101, 103, 104, 105, 106, 107, 108, 110, 111, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 289, 290, 291, 292, 293, 294, 295, 296, 297 299, 300, 301, 302, 303 or
 309. 39. The compound of claim 38 selected from a compound of Example 67, 68, 69, 70, 71, 72 Step B, 72 Step C 101, 103, 259 or
 309. 40. The compound of claim 1 selected from a compound of Examples 310 to 342, 343 to 366, 367 to 373 or 375 to
 382. 41. A method of treating tumor cells comprising administering an effective amount of a compound of claim
 1. 42. The method of claim 41 wherein the tumor cells treated are pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells, bladder carcinoma tumor cells, colon tumors cells, melanoma, breast tumor cells and prostate tumor cells.
 43. A method of treating tumor cells wherein the Ras protein is activated as a result of oncogenic mutation in genes other than the Ras gene, comprising administering an effective amount of a compound of claim
 1. 44. A method of inhibiting farnesyl protein transferase comprising the administration of an effective amount of the compound of claim
 1. 45. A pharmaceutical composition for inhibiting farnesyl protein transferase comprising an effective amount of compound of claim 1 in combination with a pharmaceutically acceptable carrier.
 46. A method of treating tumor cells comprising administering an effective amount of a compound of claim
 38. 47. The method of claim 46 wherein the tumor cells treated are pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells, bladder carcinoma tumor cells, colon tumors cells, melanoma, breast tumor cells and prostate tumor cells.
 48. A method of treating tumor cells wherein the Ras protein is activated as a result of oncogenic mutation in genes other than the Ras gene, comprising administering an effective amount of a compound of claim
 38. 49. A method of inhibiting farnesyl protein transferase comprising the administration of an effective amount of the compound of claim
 38. 50. A pharmaceutical composition for inhibiting farnesyl protein transferase comprising an effective amount of compound of claim 38 in combination with a pharmaceutically acceptable carrier.
 51. A method of treating tumor cells comprising administering an effective amount of a compound of claim
 34. 52. The method of claim 51 wherein the tumor cells treated are pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells, bladder carcinoma tumor cells, colon tumors cells, melanoma, breast tumor cells and prostate tumor cells.
 53. A method of treating tumor cells wherein the Ras protein is activated as a result of oncogenic mutation in genes other than the Ras gene, comprising administering an effective amount of a compound of claim
 34. 54. A method of inhibiting farnesyl protein transferase comprising the administration of an effective amount of the compound of claim
 34. 55. A pharmaceutical composition for inhibiting farnesyl protein transferase comprising an effective amount of compound of claim 34 in combination with a pharmaceutically acceptable carrier. 